US20080051680A1 - Apparatus for Treatment of Dermatological Conditions - Google Patents

Apparatus for Treatment of Dermatological Conditions Download PDF

Info

Publication number
US20080051680A1
US20080051680A1 US11/664,098 US66409805A US2008051680A1 US 20080051680 A1 US20080051680 A1 US 20080051680A1 US 66409805 A US66409805 A US 66409805A US 2008051680 A1 US2008051680 A1 US 2008051680A1
Authority
US
United States
Prior art keywords
skin
ultrasound
treatment
composition
carnosine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/664,098
Other languages
English (en)
Inventor
Peter Luebcke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SONOVIA HOLDINGS LLC
Original Assignee
SONOVIA Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SONOVIA Ltd filed Critical SONOVIA Ltd
Assigned to DERMAGLAIA LTD. reassignment DERMAGLAIA LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LUEBCKE, PETER
Publication of US20080051680A1 publication Critical patent/US20080051680A1/en
Assigned to SONOVIA LIMITED reassignment SONOVIA LIMITED CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: DERMAGLAIA LTD.
Assigned to SONOVIA HOLDINGS, LLC reassignment SONOVIA HOLDINGS, LLC DEED OF ASSIGNMENT OF PATENT RIGHTS Assignors: SONOVIA LTD.
Assigned to SONOVIA HOLDINGS LLC reassignment SONOVIA HOLDINGS LLC CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF THE ASSIGNEE FROM SONOVIA HOLDINGS, LLC TO SONOVIA HOLDINGS LLC PREVIOUSLY RECORDED ON REEL 027307 FRAME 0586. ASSIGNOR(S) HEREBY CONFIRMS THE DEED OF ASSIGNMENT OF PATENT RIGHTS. Assignors: SONOVIA LTD.
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0004—Applications of ultrasound therapy
    • A61N2007/0008—Destruction of fat cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0073—Ultrasound therapy using multiple frequencies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0078—Ultrasound therapy with multiple treatment transducers

Definitions

  • This invention relates to ultrasound delivery apparatus, methods and topical compositions for the treatment of skin, in particular for the treatment of cosmetic skin conditions and to improve the appearance of sun damaged and/or aged skin; the invention further relates to the use of such apparatus and compositions in methods of treating skin, which methods may incorporate the application of ultrasound.
  • the skin is a potential route for delivery of pharmaceutical or cosmetically active agents to the body.
  • the skin is not generally thought of as an efficient delivery route, due to the low permeability of the stratum corneum and the epidermis in general.
  • topical application of pharmaceutical therapeutic agents has been targeted at localized dermatological sites. More recently, transdermal techniques have been used for systemic targeting especially as this route bypasses the hepatic circulation where degradation of the active agent may occur.
  • Ultrasound can be used to deliver molecules to within the skin. When ultrasound is used in this context it is termed “sonophoresis”. Ultrasound applied to the skin has two main effects. First, cavitation results from the rapidly oscillating pressure field, causing bubble formation and collapse, which mechanically creates channels through the stratum corneum. The second effect is the direct heating of the material through which the sound waves are travelling, due to attenuation of the acoustic energy through reflection, absorption and dispersion. In skin, this occurs up to four times more than other tissues due to its heterogeneity. Heating is known to disrupt the lipid bilayer system in the stratum corneum also contributing to the enhanced permeability of the epidermis. Several factors can affect the heating capacity of ultrasound, including:
  • the permeability of the skin is increased by disruption of the intercellular lipids through heating and/or mechanical stress, and through the increase in porosity. Temperature rises of 6° C. (1 MHz, 0.25 W/cm 2 ) to 500C (20 kHz, 10-30 W/cm 2 ) have been reported, but rises as little as 11° C. (1 MHz, 2 W/cm 2 ) have been shown to cause skin damage. Continuous mode ultrasound at an intensity of 1 W/cm 2 raises the temperature of tissue at a depth of 3 cm to 40° C. in 10 minutes.
  • enhancement of permeation through the skin occurs when ultrasound is applied as a pre-treatment or simultaneously with application of the molecule; whereas for large molecules such as insulin, enhancement of permeation has only been recorded during application of ultrasound.
  • Ultrasound can be used to improve transdermal drug delivery.
  • WO 99/34857 discloses transdermal drug delivery of various active agents using a power density of less than 20 W/cm 2 , preferably less than 10 W/cm 2 ; the frequency used being less than 2.5 MHz, preferably less than 2 MHz, preferably less than 1 MHz, most preferably 20-100 kHz; Experimental data in vivo on rats was generated using a frequency of 20 kHz and a power density of 1 or 1.5 or 7 W/cm 2 .
  • U.S. Pat. No. 4,767,402 describes transdermal drug delivery using ultrasound at a power density of 0-3 W/cm 2 , preferably 0.5-1.5 MHz, and recommends that as the power density is reduced, the frequency should also be reduced.
  • a power density of 1-2W/cm 2 at frequency 870 kHz is exemplified.
  • Cosmetic treatments that aim to improve skin quality are also hindered by the barrier function of the epidermis and in particular the outer stratum corneum.
  • the epidermis provides a significant mechanical and chemical barrier to solute transfer due to the cornified cell/lipid bilayer.
  • there is significant enzymatic activity in the epidermis and dermis which provides a biochemical defence to neutralise applied xenobiotics and which is comparable to that of the liver in terms of activity per unit volume.
  • the molecular weight of active substances is known to be important in determining their propensity to diffuse across the skin. Diffusion of substances of molecular weight around 500 Da and above is known to be inefficient. Methods and apparatus involving ultrasound have been described for use in cosmetic of the skin and in medical treatments.
  • U.S. Pat. No. 6,113,559 discloses a method and apparatus of reducing wrinkles by application of a focused ultrasound beam (ultrasound power density 100-500 W/cm 2 , frequency 1-500 MHz) to a region of skin, so that the energy delivered to the dermis layer is sufficient to heat the tissue in order to stimulate or irritate the dermis layer, causing a change in the dermis layer that confers a change in smoothness of the epidermis layer.
  • a focused ultrasound beam ultrasound power density 100-500 W/cm 2 , frequency 1-500 MHz
  • Ultrasound therapy for the treatment of cellulite is well known and the application of ultrasonic wave energy has generally proven effective in breaking down subcutaneous fatty tissue.
  • EP 0 695 559 relates to multifunctional equipment for treatments of cellulite, which can include emitters of ultrasonic vibrations for application to, for example, the thighs of a patient's body.
  • suitable power densities and frequencies are not discussed.
  • GB 2303552 discloses ultrasound apparatus useful for the non-invasive reduction of cellulite.
  • the ultrasound devices are used for the ultrasonic treatment of cellulite at a predetermined frequency of about 3.3 MHz and a typical power density of 2.8 W/cm 2 , with 50% of the energy being absorbed within a depth of from 1.27 cm to 2.54 cm below the skin surface.
  • U.S. Pat. No. 6,030,374 discloses a method for enhancing transport of an active agent through the skin by exposing skin to ultrasound and applying an active agent to the skin by injection.
  • the active agent may be used to reduce the appearance of cellulite.
  • For lower frequency ultrasound an ultrasound frequency between 25 kHz and 3 MHz at a power density of 0.5-2.0 W/cm 2 is used; for higher frequency ultrasound, an ultrasound frequency between 3 MHz and 16 MHz at a power density of 0.2-1.0 W/cm 2 is used.
  • U.S. Pat. No. 5,665,053 relates to an endermology body massager having ultrasound generators that are selectively controlled by the operator.
  • the very low frequency long wave ultrasound disclosed, 10 to 40 kHz, is in the range generally recognised as being disruptive ultrasound, which may be damaging to cells, and thus for safety reasons this is not suitable for general use except at very low power levels.
  • U.S. Pat. No. 5,507,790 discloses apparatus for focusing ultrasound energy such that the temperature of a site within the patient's subcutaneous adipose tissue layer is raised to between 40.0 and 41.5° C., to accelerate local fat tissue lipolysis reaction rates.
  • the apparatus includes an ultrasonic transducer which supplies ultrasound energy of an undisclosed frequency and at an undisclosed power density to a focusing element.
  • WO 99/56829 discloses ultrasound bandages and ultrasound transducer array bandages which are said to be useful to accelerate the healing of wounds by positioning the ultrasound bandages and ultrasound transducer array bandages adjacent to a wound and generating ultrasonic pulses.
  • WO 99148621 describes large-area flexible piezoelectric composite transducer elements and large-area arrays of such transducer elements have sufficient flexibility to conform to the contours of the human anatomy, e.g., the hip, spine.
  • treatment for cosmetic skin conditions such as skin ageing and sun damage
  • the deterioration of human skin due to natural or ‘intrinsic’ ageing is characterised by a number of symptoms. Such symptoms include a thinning of both the epidermis and the dermis, a flattening of the junction between them, poor wound healing, thermoregulation and immune function along with a deterioration of associated mechanical properties such as tear resistance, elasticity and barrier function.
  • the visible appearance also deteriorates giving a rougher, lined and dry appearance along with uneven pigmentation. In most cases skin ageing is of little medical importance except in such cases as impaired wound healing which allows infection and dysfunction.
  • Visible deterioration in skin with age is due to a combination of several changes which happen more or less concurrently. This deterioration can be accelerated by lifestyle choices such as smoking and sunbathing.
  • the visibly apparent changes include: sagging skin, rough skin texture, dyspigmentation, dull complexion and a general loss of radiance. Wrinkling, or rhytide formation, is probably the symptom most commonly associated with skin ageing and is known to be caused by a change in the type and distribution of matrix proteins and proteoglycans.
  • functions of the skin that decline with age include: cell replacement, immune recognition, sensory perception, injury response, vascular responsiveness, vitamin D production, barrier function, thermoregulation, sebum production, chemical clearance, sweat production and mechanical protection. There may also be changes in pH (from 4.5 to 5).
  • Ageing skin is characterised by decreased epidermal thickness and proliferation along with the flattening of the rete ridge pattern.
  • the apparent thinning may be linked to increased apoptosis in the basal and spinous layers, in conjunction with impaired cell proliferation of the basal layer.
  • Senescent skin thins, becomes less elastic and has reduced barrier function. This is because the dermis contains a reduced cellular content with stiff, inflexible matrix proteins and a diminished number of capillary loops.
  • the overlying epidermis consequently suffers because the dermal-epidermal junction (DEJ) flattens, resulting in a reduced contact surface area as there are fewer capillary loops in proximity to the DEJ.
  • DEJ dermal-epidermal junction
  • the skin is not only subjected to intrinsic or chronological ageing processes, but also environmental or extrinsic ones. For example, factors such as diet, pollution and smoking are known to affect the rate of skin ageing. However one factor stands out as the most potent ‘gerontogen’: sunlight. It has been suggested that approximately 80% of facial ageing is due to sun exposure.
  • Collagen, elastin and other intra- and extracellular proteins of the skin are affected resulting in solar elastosis, the build-up of localised elastic tissue in fibrous bundles throughout the dermis.
  • the UV component of sunlight has also been linked to the reduction in cellular population of the epidermis (keratinocytes) and dermis (fibroblasts). It has been suggested that this is due to the increase in programmed cell death or apoptosis.
  • the epidermis and the dermis are known to become increasingly acellular with age, which supports this hypothesis.
  • the dermis Despite the epidermis influencing the dry and rough appearance of the skin, it is the dermis that dictates the degree of surface smoothness. Reduction and/or a redistribution of matrix proteins and high water-binding proteoglycans largely govern the appearance of wrinkles and general surface smoothness.
  • scarring of the skin is due to abnormal protein content, conformation and distribution via the formation of granulation tissue following trauma, again primarily a dermal rather than an epidermal problem.
  • Typical symptoms of photoageing include coarseness, wrinkling, irregular pigmentation, telangiectasia, scaliness and a variety of benign, premalignant and malignant neoplasms.
  • Photoageing is predominant in fair-skinned Caucasians who have a history of sun-exposure and occurs most severely on the face, neck and extensor surfaces of the upper extremities. Elastosis, recognised as the pebbly goose flesh seen on the neck and upper chest, is due to nodular aggregations of altered elastin fibres in the dermis.
  • a proliferation of increasingly thickened and tangled elastin fibres has been observed in the papillary and reticular dermis of sun-exposed skin. Even in mildly sun-damaged skin, a 5-20 fold increase in elastin fibre diameter has been found, with slight changes in the fibrillar structure and an alteration of the normal architecture, giving a disrupted and “moth-eaten” appearance.
  • photodamage is manifested by the progressive injury to dermal fibroblasts with quantitative and qualitative alterations to the supporting extracellular matrix. As solar energy passes through the skin and is absorbed a gradient of damage occurs, the most damage being seen in the outer papillary dermis, with less to the deeper reticular dermis.
  • Intrinsic (chronological) aging is characterised by atrophy of skin with loss of elasticity and reduced metabolic activity. Specifically, the stratum corneum remains unchanged, but the epidermis thins overall, with a flattening of the dermal-epidermal junction resulting in increased fragility of the skin. Dermal thickness and dermal vascularity are decreased; this is accompanied by a decrease in the number and the biosynthetic activity of dermal fibroblasts. This later change is manifested by delayed wound healing. Increasing age also has the effect of reducing the response of keratinocytes and fibroblasts to growth factors.
  • the concentration of fibrillin in photoaged skin has been found to be decreased and has proved to be a useful biomarker for photoageing as it is known to be connected with wrinkle formation. Fibrillin concentration is also reduced in skin that has been subjected to tensile stress and exhibits stretch marks (striae distensae).
  • In vivo proteins are post-translationally modified by a non-enzymatic reaction (Maillard reaction) between proteins (both intra- and extracellularly) and sugars.
  • This reaction is known either as glycation, or glycosylation, and is well recognized to play an important part in protein turnover, tissue remodelling, diabetes and ageing. In skin, this process is exacerbated by UV, with dermal glycation often increasing significantly after 35 years.
  • AGEs cytotoxic Advanced Glycation End-products
  • CML carboxymethyllysine
  • AGEs The build-up of AGEs has several effects. Advanced glycation end product-modified proteins are endogenous sensitizers of photo-oxidative cell damage in human skin by UVA-induced generation of reactive oxygen species (ROS) contributing to photoageing and photocarcinogenesis. ROS generation has also been linked to early and late stages of AGE formation with a direct link with the rate of ROS generation which in turn increases matrix metalloproteinase expression with a consequent decrease in healthy digestible matrix.
  • ROS generation has also been linked to early and late stages of AGE formation with a direct link with the rate of ROS generation which in turn increases matrix metalloproteinase expression with a consequent decrease in healthy digestible matrix.
  • MMPs matrix metalloproteinases
  • Cross-linking AGEs include species such as pentosidine.
  • Non-cross-linking AGEs include species such as CML. Glycation also decreases water accessibility of proteins making them more heat stable and less likely to be thermally denatured.
  • the body has a host of physiological mechanisms that defend against deleterious protein modifications, including protein-digesting enzymes.
  • Timely proteolysis removes damaged proteins before they undergo oxidative damage and cross-linking. Therefore, rapid effective proteolysis is essentially an anti-aging mechanism.
  • proteins such as collagen and elastin, which have been post-translationally modified through UV-induced glycation, are more resistant to digestion by endogenous enzymes (e.g. metalloproteinases). This, coupled with the increase in expression of such enzymes, further reduces the ratio of healthy digestible matrix proteins to modified deleterious proteins.
  • HSPs Heat Shock Proteins
  • stress proteins are thought to act as molecular chaperones by assisting with protein synthesis, transport, folding and degradation. They are a group of proteins that are present in all cells, in all life forms. They are induced when a cell undergoes environmental stress, heat, cold, or oxygen deprivation. HSPs are also present in cells under perfectly normal conditions and have been linked to modulation of contraction and relaxation responses in vascular smooth muscle; they play an important role in protein folding and function, even in the absence of stress.
  • HSPs are known to promote refolding/maintenance of conformation and also the rapid degradation of irreversibly-damaged proteins.
  • Small heat shock proteins such as ⁇ -crystallin, are known to protect eye lens proteins from glycation induced changes.
  • Small heat shock proteins are known to have common ‘crystallin’ core that appears to be responsible for the catalytic activity of these chaperones. It has been suggested that a greater understanding of ⁇ -crystallin/sHsp chaperone action will have implications for the development of therapeutics to treat and prevent cataract.
  • the heat shock protein family includes the 8-kD ubiquitin (known in connection with the ubiquitin-proteasome protein degradation pathway), 32-kD heme oxygenase-1 (connected to UVA induced oxidative stress) and HSP-47, a known collagen chaperone.
  • HSP-27 has been found in human skin and has been suggested to play a protective role in inflammatory diseases due to its links with interleukin-1 and tumour necrosis factor- ⁇ . This, along with the understanding that HSP-27 expression is closely linked with epidermal keratinocyte differentiation suggests that heat shock proteins such as HSP-27 play a role in skin protection and possibly in the UV-sunburn inflammation cycle.
  • epidermal keratinocytes are known to express HSP-72 constitutively, i.e. without exposure to previous stress.
  • the heat shock protein HSP47 has been shown to be important as a molecular chaperone for procollagen synthesis in human fibroblasts. HSP47 synthesis is reduced in aged and photo-aged skin.
  • HSP expression following exposure to UV has been linked with increased resistance to UV-induced cell death.
  • Non-toxic inducers of HSPs may protect against the immediate and long-term effects of UV exposure. Studies have shown that prior exposure of cells to red and infra-red (IR) light protects them against subsequent exposure to UV light. Similarly, IR pre-treatment of cells also protects cells against subsequent lethal (51° C.) applied heat stress.
  • IR infra-red
  • RMHS Repetitive mild heat shock
  • HSP expression Certain substances have an effect on HSP expression. For example, salicin has been shown to reduce the necessary degree of temperature rise from 42° C. to 39° C. to elicit HSP expression and to reduce the degree of subsequent UV-induced damage in cultured human fibroblasts and keratinocytes.
  • Known irritants such sodium lauryl sulphate (SLS) also induce HSP expression.
  • SLS27 upregulation due to SLS application to excised human skin has been used as a method of determining cellular stress due to chemical irritancy.
  • SLS induced expression of HSP27 in human epidermis was suppressed by topical application of vitamin C.
  • the substance zinc-L-carnosine known also as Polaprezinc commercially, has been shown to induce HSP72 (stress-induced HSP70) expression in gastric mucosa protecting cells from applied stress through chemical irritancy.
  • HSP72 stress-induced HSP70
  • ZnSO 4 and carnosine were also tested and found not to elicit the same response.
  • zinc-L-carnosine's wound-healing action has been linked to its proliferative response in non-endothelial cells such as fibroblasts.
  • HSP-72 and -70 The role of HSP-72 and -70 in conferring resistance to aspirin attack of the rat gastric mucosa has been investigated; expression of these HSPs was elevated following chronic exposure to aspirin.
  • Analgesics such as aspirin, ibuprofen and paracetamol are known to protect against cataract. This action has been attributed to the inhibition of sugar-induced cross-linking in small HSPs such as ⁇ -crystallin. Enzymes that protect against cataract are prone to glycation-induced inactivation, but aspirin has been shown to protect against this.
  • acetyl-L-carnitine has been recognised as a potential chaperone-protecting agent due to its abilities to acetylate potential glycation sites of small HSPs and correspondingly protect them from glycation-mediated protein damage.
  • Small heat shock proteins and Clusterin are molecular chaperones that share many functional similarities despite their lack of significant sequence similarity. Small heat shock proteins are ubiquitous intracellular proteins whereas clusterin is generally found extracellularly. Both chaperones prevent the amorphous aggregation and precipitation of target proteins under stress conditions such as elevated temperature, reduction and oxidation. Transcription of both HSPs and clusterin are mediated by the transcription factor HSF-1. However, clusterin has been shown to be much more efficient than certain sHSPs, such as ⁇ -crystallin, in preventing the precipitation from solution of stressed target proteins.
  • Clusterin is expressed as a 75-80 kDa heterodimeric protein that is heavily glycated such that 30% of its mass is comprised of sugar. Whereas the chaperone activity of small heat shock proteins such as ⁇ -crystallin is reduced significantly at lower pH, the activity of clusterin is enhanced at lower pH. This has important implications for sites of tissue damage or inflammation where local acidosis (pH ⁇ 6) occurs. Another similarity that clusterin shares with sHSPs is the ability to regulate apoptosis. Over-expression of clusterin can protect cells from a variety of agents (e.g. TNF- ⁇ and UV irradiation) that otherwise induce apoptosis. It has been suggested that clusterin may interact with stressed cell surface proteins to inhibit pro-apoptotic signal transduction or prevent inappropriate interactions of intracellular proteins during stress.
  • agents e.g. TNF- ⁇ and UV irradiation
  • the invention provides an apparatus for application of ultrasound to the skin comprising a plurality of ultrasound transducer elements arranged as an array in a flexible material in spaced configuration, wherein the ultrasound transducer elements are capable of delivering ultrasound at low and/or high frequency to an area of the skin.
  • an ultrasound array can be incorporated into a mask, patch or patches that can be applied to the skin to supply ultrasound.
  • the mask or patch is preferably shaped to conform to at least part of the surface of the face.
  • the flexible array of ultrasound transducer elements can be formed in a circular or any other simple or complex shape, especially those optimised to conform to bodily shapes and features, especially the parts of the face and neck.
  • the array should be sufficiently flexible to allow bending to a curvature of 3-4 cm radius, preferably to allow bending to shape around doubly curved surfaces as well as singly curved surfaces.
  • Application of ultrasound using an apparatus according to the invention can be used as a pre-treatment before application of a composition of the invention, or a composition of the invention can be applied to the skin, either directly or via material impregnated with the composition, e.g. a pad, such as a gel pad, and then the ultrasound delivered via the flexible array.
  • the flexible ultrasound array can be coupled to a thin (2-3 mm), disposable gel pad that contains the composition and couples the ultrasound energy.
  • the flexible array can be affixed, directly or indirectly (e.g. via a pad) to the skin for the duration of the treatment.
  • the transducer elements of the array are preferably hermetically sealed, e.g. contained within a waterproof flexible material capable of electrical performance even when adhered/coupled to aqueous formulations.
  • the flexible material is at least approximately acoustically matched, to one or preferably both of the transducer elements, to inhibit generation of reflections in the material that might divert or otherwise dissipate the ultrasound waves.
  • the flexible material may comprise a polymeric material selected from thermoplastics, thermosets, rubbers or mixtures thereof.
  • the flexible acoustically matched material will ordinarily be formed from a polymeric material, and optionally, a filler.
  • the polymeric material should have good compatibility with the components of the transducer element, biocompatibility and flexibility.
  • Suitable polymeric materials include thermoplastics such as high density polyethylenes, polymethyl methacrylates, polypropylenes, polybutylene terephthalates, polycarbonates, polyurethanes such as CA 118 and CA 128 available from Morton Chemical and estane polyester, and the like; thermosets such as epoxies such as Spurr epoxy and Stycast 80, Stycast 1365-65 and the like; and rubbers such as silicone rubbers such as dispersion 236 available from Dow Corning and RTV-141 available from Rhone-Poulenc, Inc. and the like. If desired, the acoustic impedance of the polymeric materials may be increased by the incorporation of one or more fillers.
  • Suitable fillers include PZT, tungsten, alumina, silica glass, tungsten carbide, titanium, glass powder and the like with glass powder being preferred.
  • the size of the filler particles should be in the range of about 0.1 to about 50 microns and preferably from about 0.5 to about 5 microns.
  • the amount of filler employed will be that amount necessary to impart the desired acoustic impedance. Normally, from about 2 to about 50 percent filler by volume and preferably from about 5 to about 30 volume percent filler is employed.
  • a preferred polymeric material is silicone rubber.
  • the transducer elements will be individually connected to a ultrasound generator, such that the ultrasound transducer elements are capable of delivering low and high frequency ultrasound simultaneously or sequentially.
  • An apparatus can comprise a flexible array having a set of high frequency transducer elements and a set of low frequency transducer elements respectively capable of delivering high and low frequency ultrasound.
  • the high and low frequency transducers may be alternated, or otherwise arranged in a pattern, for example a substantially regular arrangement of the two types of transducers.
  • the high and low frequency elements may be mounted together, e.g. on top of one another, in particular coaxially.
  • the transducer elements may be dual frequency transducer elements capable of delivering low and high frequency ultrasound sequentially or simultaneously, along a single axis. Dual frequency transducers may be arranged in a pattern, for example a substantially regular arrangement of dual frequency transducers.
  • Transducers may be of circular or other regular or irregular shape.
  • Transducers elements suitably comprise transducer materials known in the art, e.g. piezoceramics, PVDF, and/or piezoelectric materials such as PZT powders commercially available from Morgan Matroc, Inc., ceramic, single crystal relaxor ferroelectric, lead zirconate titanate Pb (Zr, Ti) 03, lead metaniobate Pb (Nb206), modified lead titanate PbTi3 such as (Pb, Ca)Ti03 and (Pb, Sm)Ti03, barium titanateBaTiO3, PMN-PT(1-x) Pb(Mg′′3Nb2/3) 03-xPbTi03, PZN-PT/BTNb2/3)03-x(yPbTiO3-(1-y)PbZrO3)Pb(Zn1/3Nb2/3)O3-xPbTiO3-BaTiO3,(1-x)Pb
  • transducer elements can be capable of delivering the low frequency component in pulsed mode and the high frequency component in continuous mode, or more preferably capable of delivering the low frequency ultrasound component in continuous mode and the high frequency ultrasound component in pulsed mode.
  • the pulsed mode can be controllable, such that it is variable, to provide variable pulsing regimes, for example 2 ms on, 8 ms off (20% duty cycle).
  • the transducer elements are capable of delivering a low ultrasound frequency of from 20 to 500 kHz, preferably ⁇ 50 kHz and/or a high ultrasound frequency of from 0.5 to 3.5 MHz, preferably ⁇ 1 MHz up to 3 MHz.
  • the spatial average power density of the low frequency ultrasound energy is suitably from 20 to 500 mW/cm 2 .
  • the spatial average power density of the high frequency ultrasound energy is suitably from 0.5 to 3 W/cm 2 .
  • the invention provides a dual frequency transducer element comprising a high frequency transducer element and a low frequency transducer element, preferably the high and low frequency transducer elements are co-axially mounted and may be mechanically and electrically connected,
  • the high frequency transducer element comprises a piezo ceramic material and the low frequency transducer element comprises PVDF.
  • the high and low frequency transducer elements can be bonded together, optionally with a spacer element in between, which may be a metal spacer element.
  • An apparatus according to the invention may comprise an array of dual frequency transducer elements as described herein.
  • the ultrasound array can be programmed to deliver a desired sequence of high and/or low ultrasound frequencies, in pulsed or continuous mode, in set patterns, thereby avoiding problems of over or under exposure of the skin the ultrasound, which can cause over-heating of the skin.
  • An apparatus of the invention is controllable such that low and high frequencies are capable of being driven so that the ultrasound field moves across the array in a preset pattern and at a preset speed, for example 2-3 seconds from left to right across the full width (e.g. 5-10 cm) of the array then 2-3 seconds back again, i.e. 4-6 seconds cycle time; or into the centre of the array and then out again, especially if the array has circular shaped geometry.
  • the pattern can be varied within the same treatment session, e.g. left to right then up and down.
  • the high and low frequencies are applied so that each frequency covers the area being treated as evenly as possible.
  • the flexible array is preferably configured such that ultrasound is not applied to the eye and such that the transducers will be sited and controlled so that the possibility of over exposure of skin which is in proximity to bone to ultrasound (e.g. cheek bones or the orbit of the eye) is minimised. This can be achieved by application of ultrasound in pulsed mode and for example by a delivering ultrasound in a pre-determined phased array sequence. Use of a mask, patch or patches to apply ultrasound is particularly suitable for home use.
  • the apparatus may comprise a power and control unit, which is suitably of an appropriate size to enable it to be held in the hand.
  • the unit is preferably provided in a waterproof wipe-clean casing. Power may be supplied from batteries, e.g. rechargeable batteries, to allow use away from mains supply.
  • the unit is preferably provided with controls to allow the user to select settings for a desired treatment, these may include pre-set levels to enable the user to select settings for different uses, e.g. for anti-ageing treatments, cellulite treatment or for scar reduction, the various settings being based on different frequency and amplitude/power settings.
  • the control unit may include a maximum time cut-out to prevent over-exposure, e.g. 10 minutes.
  • a memory function may be provided, e.g. to record date and/or duration of treatment
  • the invention relates to an ultrasonic treatment system comprising a plurality of transducer elements ( 15 ) arranged as an array ( 2 ) and held in proximity to each other by compliant material ( 4 ), which is suitably silicone rubber ( FIGS. 1 a, b and c ).
  • Each element ( 15 ) may comprise two components, a high frequency transducer element, e.g. a piezo ceramic disc element ( 5 ) and a low frequency transducer element, e.g. a pvdf element ( 7 ) positioned so that the positive polarised electrode of each element is mechanically and electrically connected at interface ( 9 ).
  • the upper surface ( 30 ) of the PZT element ( 5 ) and the lower surface ( 31 ) of the pvdf element ( 7 ) are connected together electrically ( FIG. 1 ( d )).
  • Each element ( 1 ) is individually connected to a power source described in FIG. 3 via spring connectors ( 8 ) attached to juxta-positioned contacts ( 3 ) on flexibly mounted plate ( 6 ) FIG. 1 a.
  • the transducer array may then be connected to an ultrasound generator via connectors ( 11 ).
  • FIGS. 2 a and 2 b show a particular form of the transducer element in which PZT disc ( 12 ) is conductively attached to metal element ( 13 ) which in turn is conductively attached to a pvdf material ( 24 ) via metal ring ( 23 ) and insulating spacer ring ( 22 ).
  • the common HT connection ( 9 ) is achieved via conductive ring ( 21 ).
  • Alternate drive frequencies of 50 kHz and 1 MHz are generated either by individual circuits in system FIG. 3B or via DDS chip in FIG. 3A .
  • the combined transducer is thus alternatively energised in burst of 50 kHz and 1 MHz sine wave pulses.
  • the length and ratio of activation signals may be processor controlled or derived from a sensor control related to measured characteristics of the target tissue.
  • element ( 13 ) may be formed as a focussing device by shaping the lower surface with a shaped, focussing profile, e.g. a concave profile, thus imparting similar properties to the geometrically compliant pvdf film.
  • the present invention provides a composition comprising one or more anti-glycation agent, one or more anti-oxidants, a dermatologically acceptable excipient or excipients and optionally one or more substance capable of inducing expression of a molecular chaperone.
  • compositions of the invention are useful in the treatment of cosmetic skin conditions, in particular acting to improve the appearance of ageing skin, especially by ameliorating the effects of sun damage.
  • the or each anti-glycation agent is present at from about 0.5 to 5%, preferably from about 1 to 3% w/w of the composition.
  • the anti-glycation agent(s) also has anti-oxidant activity.
  • Preferred anti-glycation agents for incorporation into compositions include one or more of a histidine containing dipeptide, alanyl-L-histidine (L-carnosine) or a peptidomimetic thereof, N-acetylcysteine, aminoguanidine, d-penicillamine, acetylsalicyclic acid (aspirin), paracetamol, indomethacin and ibuprofen and/or a functional homolog; derivative or prodrug thereof.
  • a histidine containing dipeptide alanyl-L-histidine (L-carnosine) or a peptidomimetic thereof
  • N-acetylcysteine aminoguanidine
  • d-penicillamine acetylsalicyclic acid
  • paracetamol indomethacin and ibuprofen and/or a functional homolog
  • derivative or prodrug thereof include one or more of a histidine containing dipeptid
  • L-carnosine ⁇ -alanyl-L-histidine, or “carnosine”
  • Carnosine present at high concentrations in skeletal muscle tissue, can delay senescence and provoke cellular rejuvenation in cultured human fibroblasts. The mechanism by which such a simple molecule induces these effects is not known despite carnosine's well documented anti-oxidant and oxygen free-radical scavenging activities.
  • it may also directly participate in the inactivation/disposal of aged proteins possibly by direct reaction with the carbonyl groups on proteins.
  • the possible fates of these carnosinylated proteins include the formation of inert lipofuscin, proteolysis via the proteasome system and exocytosis following interaction with receptors
  • carnosine may tag glycated proteins for removal. Protein turnover relies on hydration for thermal denaturation and glycated proteins are known to have higher enthalpies of denaturation obviously rendering them less degradable. ‘Carnosinylation’ of glycated proteins, it has been suggested, may increase the water accessible surface of such proteins and therefore promote hydration and unfolding during thermal denaturation. This theory has been borne out by observing lower ⁇ H and ⁇ G denaturation for carnosinylated glycated proteins.
  • Carnosine acts as an anti-glycation agent, it inhibits carbonyl attack by methylglyoxal (MG) and by the AGE carboxymethyl lysine (CML).
  • Carnosine itself has been shown to be readily glycated by a variety of sugars forming non-mutagenic adducts and its protective role has been attributed to effect of preventing glycation of crystalline superoxide dismutase (SOD) and catalase.
  • SOD superoxide dismutase
  • Carnosine has been found to offer a superior efficacy and toxicity profile when compared to the anti-glycation agent aminoguanidine, thus carnosine is a preferred anti-glycation agent.
  • Carnosine exhibits Mn + chelation and ROS scavenging properties, but these alone cannot adequately explain the effect it has in rejuvenating senescent fibroblasts.
  • One study has attributed its properties to the reaction of carnosine with carbonyl groups on glycated/oxidised proteins and other molecules; this reaction, termed ‘carnosinylation,’ inhibits cross-linking of glycoxidised proteins to normal macromolecules; and carnosinylation could affect the fate of glycoxidised polypeptides.
  • Studies on rat embryonic fibroblasts demonstrated that L-carnosine sustains the retention of cell morphology even during a nutritional insult for five weeks.
  • L-carnosine significantly reduces the formation of 8-hydroxy-deoxyguanosine (8-OH dG) in the cells after four weeks of continuous culture.
  • 8-OH dG 8-hydroxy-deoxyguanosine
  • Carnosine also extends cultured human fibroblast life-span, kills transformed cells, protects cells against aldehydes and an amyloid peptide fragment and inhibits, in vitro, protein glycation and DNA/protein cross-linking. Fibroblasts retain a juvenile appearance in the presence of carnosine, and revert to a senescent phenotype when carnosine is removed.
  • carnosine In addition to anti-glycation anti-oxidant activity, carnosine also has an anti-inflammatory action. Denatured protein at the site of inflammation is more susceptible to glycation, hence the anti inflammatory effect may enhance the inhibition of glycation.
  • Carnosine is water soluble and this suggests that it may represent the aqueous phase counterpart to lipid-soluble antioxidants such as ⁇ -tocopherol which act to protect cell membranes.
  • Carnosine, and carnosine-related compounds (CRCs) imidazole, histidine, anserine
  • CRCs carnosine-related compounds
  • Carnosine has been shown to complex Cu 2+ dimerically, this may explain why carnosine reduces free radical production, as metal complexing will reduce available levels of Cu 2+ and Fe 2+ which would otherwise be coordinatively bonded by AGEs in proteins (the imidazole ring of carnosine can be compared with that of the many different imidazole containing AGE X-links) leading to hydroxyl and other reactive oxygen species production in situ. Carnosine also interferes with iron/ascorbate induced phospholipid oxidation.
  • Carnosine produces dose-dependent vascular relaxation (vasodilation) that is independent of endothelium.
  • carnosine's component amino acids L-histidine and alanine have been found to produce no effect and dose dependent vasoconstriction respectively.
  • Carnosine is hydrolysed physiologically into its component amino acids: histidine and ⁇ -alanine.
  • ⁇ -alanine is believed to have be involved in the promotion of collagen synthesis.
  • Histidine is known for its anti-inflammatory properties, its ability to scavenge single oxygen and interfere with redox reactions involving iron and other metal ions.
  • Carnosine has been shown to improve the rates of wound healing when given as part of a complete enteral formula, but has not to date been reported to be used topically in wound healing preparations.
  • CRCs such as the carnosine pro-drug N-acetyl-L-carnosine (NAC) undergo hydrolysis yielding carnosine in situ.
  • NAC has been shown to treat oxidative stress in ocular disorders such as cataracts and glaucoma.
  • carnosine homologs include homocarnosine and anserine which protect Cu,Zn-SOD from inactivation and prevent release of Cu 2+ .
  • Many carnosine homologs are produced by the enzyme carnosine synthetase.
  • compositions according to the invention include one or more of ⁇ -alanylhistamine (carcinine), N-acetyl- ⁇ -alanylhistamine (N-acetyl carcinine), L-prolyl histamine, and/or n-acetyl-L-carnosine.
  • L-carnosine provides a derivative with increased resistance to hydrolytic enzymes.
  • Carnosine peptidomimetics functional homologs
  • Carnosine peptidomimetics are known, which have free radical scavenging and lipid hydroperoxide deactivating properties similar to or even better than the natural carnosine peptide.
  • N-acetyl-p-alanylhistamine and L-prolylhistamine are highly effective inhibitors of lipid hydroperoxide-mediated cross-linking of a protein.
  • N-acetyl- ⁇ -alanylhistamine has been shown to protect skin enzymes from UV-induced degradation.
  • a composition according to the invention comprises one or more anti-oxidant(s), preferably selected from the group comprising: arginine, ascorbic acid, a prodrug or derivative of ascorbic acid, ascorbyl palmitate, magnesium ascorbyl phosphate, trisodium ascorbyl phosphate, anserine, carnosine, opidine, homocarnosine and/or acetylanserine.
  • the or each anti-oxidant is present at from about 0.5 to 5%, preferably from about 1 to 3% w/w of the composition.
  • Arginine is a powerful antioxidant and a very effective sacrificial target for Maillard type protein cross-linking reactions. Both arginine and lysine have been shown to be effective inhibitors of glycation, but arginine especially tends to form AGEs itself. It is known that the number and diameter of capillary loops close to the dermal-epidermal junction (DEJ) is reduced with age. The supply of nutrients and removal of by-products from metabolism and other cellular processes is consequently impaired. L-arginine acts as a vasodilator due to enzyme-catalysed formation of nitric oxide (NO) in situ. The formation of nitric oxide (NO) from L-arginine is now recognized as a ubiquitous biochemical pathway involved in the regulation of the cardiovascular, central, and peripheral nervous systems, as well as in other homeostatic mechanisms.
  • NO nitric oxide
  • Ascorbic acid (vitamin C, AA) is an essential nutrient involved in many physiological functions. It readily (yet reversibly) undergoes two consecutive, one-electron oxidation processes to form the ascorbate radical, a relatively unreactive free radical, and is therefore considered an excellent reducing agent. In living organisms, ascorbic acid can protect tissues and cells against oxidative damage by free radicals and reactive oxygen-derived species. AA is known to exert a strong UVA protecting ability in studies on eye lens proteins including X-ray irradiation.
  • ascorbic acid in solution can undergo oxidation and produce dehydro-L-ascorbic acid as well as many degradation products, which can result in browning of compositions containing ascorbic acid.
  • factors can accelerate ascorbic acid degradation such as high storage temperatures, light, high pH values and the presence of dissolved oxygen, although the reaction mechanism of ascorbic acid with an oxygen molecule has not yet been fully elucidated.
  • the reaction of ascorbic acid with oxygen is strongly catalysed by metal ions, particularly cupric and ferric ions.
  • the ascorbic acid component of a composition can be provided separately and mixed into the other components of the composition shortly before use.
  • a stable prodrug or derivative of ascorbic acid can be included in the composition as an alternative, or in addition to, ascorbic acid.
  • Ascorbyl palmitate is a fat-soluble derivative of vitamin C widely used in skin care products. It is non-irritating and more stable than ascorbic acid. Furthermore, ascorbyl palmitate is a fat-soluble antioxidant and is at least as effective as vitamin E in protecting the skin from lipid peroxidation (a key type of free radical damage in the skin).
  • Magnesium ascorbyl phosphate is a water-soluble derivative of vitamin C. It is non-irritating and more stable than vitamin C. Most importantly, magnesium ascorbyl phosphate appears to have the same potential as vitamin C to boost skin collagen synthesis but is effective at significantly lower concentrations. Most vitamin C formulas are highly acidic and therefore produce exfoliation, so magnesium ascorbyl phosphate is a preferred ascorbic acid derivative for use in compositions, particularly those for individuals with sensitive skin and those wishing to avoid exfoliating effects.
  • Trisodium ascorbyl phosphate (Stay-C® 50) is the sodium salt of the monophosphate ester of ascorbic acid. It is a pro-vitamin, with greater stability in aqueous solution than ascorbic acid. Phosphatases in the skin act on trisodium ascorbyl phosphate to release ascorbic acid.
  • compositions according to the invention may contain one or more substances capable of inducing expression of a molecular chaperone, particularly useful are substances capable of inducing expression of a heat shock protein, clusterin and/or alpha crystallin.
  • the one or more substance capable of inducing expression of a molecular chaperone can be acetyl salicylic acid, salicylic acid, zinc ions, a zinc salt, zinc sulphate, and/or zinc-L-carnosine.
  • a zinc containing agent is present at from about 0.1 to 1%, preferably from about 0.25 to 0.75%, most preferably around 0.5% w/w of the composition.
  • acetyl salicylic acid or salicylic acid is present in the composition a suitable concentration is from about 0.5 to 2.5 %, preferably from about 1 to 1.5% w/w of the composition.
  • a composition according to the invention may further comprise one or more anti-apoptotic substance, preferably selected from the group comprising nicotinoamide, L-carnitine, acetyl-L-carnitine, N-acetyl-cysteine and/or L-carnosine.
  • the or a anti-apoptotic substance is usually present at a concentration of from about 0.5 to 5%, preferably 1 to 3% of the composition.
  • the present invention provides a composition comprising one or more substance capable of inducing expression of a molecular chaperone and a dermatologically acceptable excipient.
  • a composition according to the invention may further comprise one or more ingredient selected from the group comprising one or more vitamins, one or more small peptide(s), and/or one or more amino acid(s) or a derivative or prodrug thereof.
  • Vitamins that may be incorporated into compositions of the invention include vitamin B compounds such as thiamine (vitamin B1), e.g. as thiamine pyrophosphate, such as benfotiamine; pyridoxamine (vitamin B6), vitamin A and/or E, or a derivative or prodrug thereof
  • vitamin B1 thiamine
  • thiamine pyrophosphate such as benfotiamine
  • pyridoxamine vitamin B6
  • vitamin A and/or E or a derivative or prodrug thereof
  • Pyridoxamine (B6) has been shown to effectively inhibit AGE and lipoxidation product formation, and in particular blocks formation of methylglyoxal-lysine dimer by itself forming methylglyoxal-pyridoxamine dimer.
  • Pyridoxamine (B6) and thiamine pyrophosphate (B1) have both been shown to be effective post-Amadori inhibitors of AGE formation with B6 effecting a measurable decrease in rate of AGE formation and final AGE levels and B1 effecting a measurable decrease in final AGE levels only. Both compounds show far greater potency in post-Amadori inhibition of AGE formation than aminoguanidine.
  • Thiamine derivatives such as benfotiamine (lipid-soluble prodrug of thiamine) have been identified as potential therapeutic agents in the inhibition of intracellular glycation in the treatment of vascular diabetic complications and have been shown to inhibit imidazolone-type AGE accumulation.
  • composition may comprise one or more small peptide(s) suitably as a dipeptide, tripeptide and/or tetrapeptide, and/or one or more amino acid(s), e.g. proline, lysine, histidine, alanine, or a derivative or prodrug thereof.
  • small peptide(s) suitably as a dipeptide, tripeptide and/or tetrapeptide, and/or one or more amino acid(s), e.g. proline, lysine, histidine, alanine, or a derivative or prodrug thereof.
  • a composition according to the invention may further comprise one or more polysaccharide, which may be one or more proteoglycan, such as a glycosaminoglycan.
  • the one or more glycosaminoglycan employed can be a low and/or high molecular weight hyaluronan, chondriotin sulphate, dermatan sulphate and/or one or more derivative(s) thereof.
  • compositions according to the present invention are important for providing the ‘smooth’ turgidity of skin due to hydration and are also important as intercellular reservoirs for growth factors and other cytokines.
  • PGs are synthesized by the dermal fibroblasts and have a close relationship with growth factors such as basic fibroblast growth factor (b-FGF).
  • b-FGF basic fibroblast growth factor
  • the N-terminal binding domain of collagen is affected by glycation and consequently the quantity and location of PGs in the dermis are affected by AGE accumulation.
  • HSPGs heparan sulfate proteoglycans
  • GAGs especially Hyaluronic acid
  • mucopolysaccharides only constitute 0.1-0.3% of the dry weight of the skin, any decrease can be easily understood to influence the skin turgor as the molecules bind water in the dermis up to 1000 times the volume of the molecule itself. Additionally, these substances are known to influence migration, growth and differentiation of connective tissue cells in some instances.
  • Hyaluronic Acid or Hyaluronan (“HA”) is a long-chained polysaccharide that is a major constituent surrounding cells in most animal tissues. HA is attracted to and adheres to specific receptors on cell membranes which can be found in increasing numbers at sites of damage and disease in the body with a significant amount on the skin. This means that drugs can potentially be targeted to and held at the site where the drug is needed.
  • the safety profile of HA, its ability to carry drug and its potential targeting characteristics make it an excellent vehicle for topical drug delivery. Drugs can be covatently attached to HA or contained within the X-linked networks of derivatives of HA.
  • Hyaluronan has been used for decades in cosmetics, viscosurgery and viscosupplementation without immunological reactions or any other side-effects. It is present naturally at high concentrations in connective tissues such as skin and cartilage, in the vitreous body of the eye and in synovial fluid. Usually it is bound to cells and proteins but some HA is present in the interstitial fluid. HA is a polysaccharide consisting of alternating units of glucuronic acid and N-acetylglucosamine. The carboxyl groups present are largely ionised at the pH of the skin (generally around pH 4.5 to 5.5) and it is therefore highly hydrophilic.
  • HA predispose HA to forming viscoelastic gels which have potential for surface retention, acting as a reservoir for therapeutic agents.
  • hydrophilic properties of HA it can penetrate normal epidermis and accumulate extracellularly in the dermis before disposal via known metabolic pathways.
  • a composition according to the invention will comprise a low and high molecular weight hyaluronan and/or one or more derivative(s) thereof.
  • Low molecular weight hyaluronan characteristically has a molecular weight of less than 1 ⁇ 10 6 Da, whereas a high molecular weight hyaluronan generally has molecular weight of greater than 1 ⁇ 10 6 Da.
  • HA forms a viscoelastic, smooth, lubricating film when applied to the surface of the skin, thus externally applied HA not only has a beneficial effect on the skin, but also can be used to enhance the viscosity of a composition so that on application to the skin it remains in contact with the skin in a gel-like layer. This is particularly beneficial when ultrasound is to be applied to skin treated with a composition according to the invention.
  • the HA molecule can be derivatised via modification of the acetamido, the reducing end group but most commonly the hydroxy and carboxylate groups.
  • the glycosidic bond is also readily hydrolysed to create shorter chains or oligosaccharides.
  • HA-drug adducts have been synthesised for controlled delivery applications and HA-protein adducts as biomaterials and cell substrates.
  • HA exists as Na-HA at physiological pH. It has a complete lack of immunogenicity which makes it an ideal building block for biomaterials and drug delivery systems. HA effects a controlled and sustained release of drugs through the skin by the formation of a reservoir of the drug around the basement membrane. Neither NaCMC (at a weight or Theologically equivalent concentration) nor chondroitin sulphate (at a weight equivalent concentration) exert the controlled release effect seen for the hyaluronan formulation in full thickness skin, thus HA is a particularly preferred glucosaminoglycan for the purposes of the present invention.
  • the enhancement of percutaneous absorption by HA is believed to be partly due to its ability to hydrate the skin so disrupting the compact cell/lipid layers. HA is superior to other GAGs in this respect due to its high water binding capacity.
  • Tetrasaccharides of HA have been found to exert an anti-apoptotic effect as they up-regulate HSP72 expression under conditions of stress and suppress cell death.
  • High molecular weight HA polysaccharides are generally space filling molecules with anti-angiogenic, anti-inflammatory and immunosuppressive activity.
  • Lower molecular weight fragments (6-20 kDa) are angiogenic, inflammatory and immunostimulatory.
  • HA has been shown to be depolymerised by Maillard reaction products (glucose-lysine) via a free-radical mechanism. Hydroxyl radicals depolymerise HA and have been linked to inflammation in arthritis and the breakdown of synovial fluid. High (but not low) molecular weight HA and derivatives of HA such as BEHA act as antioxidants scavenging reactive oxygen species (ROS) such as O 2′ z,900 and OH, which otherwise would impair the migratory and proliferative properties of dermal fibroblasts thereby prolonging inflammation and delaying wound healing.
  • ROS reactive oxygen species
  • Hyaluronans have the ability to increase proteoglycan synthesis, stimulate tissue inhibitor of metalloproteinase-1, has the ability to stimulate collagen remodelling, to enhance cell migration, stimulates wound healing by upregulating the expression of transforming growth factor- ⁇ .
  • Low-molecular weight HA ( ⁇ 300 kDa) is available from Sigma, Poole, Dorset (isolated from bovine vitreous humor). High molecular weight HA is available from ConvaTec, Flintshire, UK (isolated from human umbilical cord). Commercially available HA preparations are given in tables 1a, 1b and 1c. TABLE 1a Examples of NaHA used in the clinical treatment of osteoarthritis Trade name Molecular weight of NaHA* Manufacturer Artz ® 600,000-1,200,000 Seikagaku (Japan) Hyalgan ® 500,000-730,000 Fidia (Italy) Synvisc ® mildly cross-linked HA Biomatrix (USA)
  • HAs include NIF-NaHA marketed under the name of Healon® for medical and Hylartil® for veterinary use; Hylan A (elastoviscous fluid) and Hylan B (viscoelastic gel) developed by Biomatrix Inc.
  • a dermatogically acceptable excipient or excipients suitable for use in a composition according to the invention include water, a water/ethanol mixture (e.g. up to 25%, preferably up to 20% ethanol in the composition % w/w), a viscous gel or emulsion, an aqueous gel, a hydrogel, a water-based emulsion in the form of a cream or application, an oil-in-water emulsion in the form of a cream or application, or a jelly.
  • a water/ethanol mixture e.g. up to 25%, preferably up to 20% ethanol in the composition % w/w
  • a viscous gel or emulsion e.g. up to 25%, preferably up to 20% ethanol in the composition % w/w
  • a viscous gel or emulsion e.g. up to 25%, preferably up to 20% ethanol in the composition % w/w
  • a viscous gel or emulsion e.
  • a composition which is to be applied in conjunction with ultrasound treatment will have a viscous nature, so that a layer of the composition can be spread on the skin and will remain in place on the skin until it is removed, e.g. by wiping the composition away with tissue or cotton wool, or by rinsing the formulation off.
  • a composition according to the invention may comprise a film-forming ingredient.
  • One or more ingredient selected from: a sun block, humectant, pigment, foundation or concealer pigment, fake tan pigment or composition may be included in a composition according to the invention.
  • a composition according to the invention is preferably at a pH close to the pH of skin, e.g. at a pH of from pH 4 to pH 6, or pH 4.5 to pH 5.5.
  • the present invention provides a method for treatment of the skin, comprising applying to the skin a composition according to the invention.
  • the method is a method of cosmetic treatment of cosmetic skin conditions.
  • the invention also encompasses the treatment of medical skin conditions, in which instances the method is a method of medical treatment.
  • a method for treatment of the skin may further comprise application of ultrasound directly or indirectly to an area of skin to which the composition has been applied, or as a pre-treatment to an area of skin to which the composition is to be applied.
  • application of ultrasound is performed at low and/or high frequency directly or indirectly to an area of the skin where the composition has been applied, or is to be applied.
  • Low and high frequency ultrasound can be applied simultaneously, sequentially or separately, e.g. sequentially as several alternating single applications of low and high frequency or, separately where a series of applications of low frequency is alternated with a series of applications of high frequency.
  • Low frequency ultrasound is believed to be useful to facilitate delivery of molecules to the skin (a process termed “sonophoresis”).
  • High frequency ultrasound has a lesser sonophoretic effect than low frequency, but it also has many other effects beneficial to the skin in that it stimulates fibroblast proliferation, stimulates collagen and other extracellular matrix (ECM) component formation (e.g.
  • HSPs Heat Shock Proteins
  • low and high frequency ultrasound is applied simultaneously.
  • the low frequency component of the ultrasound is preferably applied in continuous mode and the high frequency component is preferably applied in pulsed mode.
  • a low ultrasound frequency is from 20 to 500 kHz, the spatial average power density of the low frequency ultrasound energy being from 20 to 500 mW/cm 2 ;
  • a high ultrasound frequency is from 500 kHz (0.5 MHz) to 3.5 MHz, the spatial average power density of the high frequency ultrasound energy being from 0.5 to 3 W/cm 2 .
  • the beam is not focussed and is diverging.
  • the target rise in skin temperature is up to 42 or 43° C., but preferably no higher.
  • Single areas of skin are insonated for a minimum of 5 minutes, preferably 10 minutes, or a time between 5 and 12 minutes.
  • ultrasound can be applied using a hand-held applicator, optionally adapted for application of a composition according to the invention to the skin.
  • a cartridge/dispenser can be attached to the ultrasound head such that the formulation is gradually released as the head is moved around the skin surface, the cartridge may contain a pre-set amount of formulation.
  • Different cartridges with different formulations can be attached depending on the skin condition being treated, e.g. different cartridges may contain different compositions for anti-ageing treatments, the treatment of scars, stretch-marked skin or cellulite.
  • the ultrasound is applied by gently massaging the ultrasound applicator on the skin in a circular or linear stroking movement.
  • Ultrasound can be applied as a pre-treatment, before application of a composition of the invention.
  • a layer of the composition or a material impregnated with the composition can be applied to the skin during or prior to the application of ultrasound.
  • the applicator When using an applicator, the applicator is moved across the skin so that no single area is over-exposed to ultrasound, which could cause overheating.
  • the combination of ultrasound and the mechanical stimulus afforded by the massaging action helps to stimulate the skin to encourage renewal and repair.
  • Ultrasound can be applied by applied by immersion of the area to be treated in an ultrasound bath, e.g. directly by immersing bare skin in a composition of the invention, or by coating the skin with the composition, wrapping the part to be treated, and immersion in a liquid that can transmit ultrasound energy.
  • an apparatus for application of ultrasound to the skin may comprise a plurality of ultrasound transducer elements arranged as an array in a flexible material in spaced configuration, wherein the ultrasound transducer elements are capable of delivering ultrasound at low and/or high frequency to an area of the skin.
  • Skin treatment using these method can be performed in a beauty clinic or in a medical clinic such as a hospital clinic, or in a doctor's surgery.
  • a circular area of skin 2 to 3 cm in diameter should be subjected to ultrasound for a minimum of 5 minutes, preferably 10 minutes or a time between 5 and 12 minutes.
  • a suitable ultrasound device for use in methods of the invention is an ultrasound array incorporated into a mask or patch as described herein; or a device which can generate low and high frequency outputs and has a handset designed to give combinations of output frequencies and energies, such as the Duo SonTM unit (Orthosonics, Devon UK).
  • the Duo SonTM unit can be used either at the current specification (described in Table 2), or at a slightly altered specification dictated by optimisation of frequency, wattage and duty cycle parameters to enhance actives delivery and cell/protein stimulation. Such adjustments remain within the guidelines for CE marking of the unit.
  • US ultrasound
  • sonophoresis for delivery of molecules to the skin
  • cavitation results from the rapidly oscillating pressure field causing bubble formation and collapse which mechanically creates channels through the stratum corneum.
  • the second effect is actual direct heating of material through which the sound waves are travelling due to attenuation of the acoustic energy through reflection, absorption and dispersion. This occurs in skin up to four times more than in other tissues due to its heterogeneity. Heating is known to disrupt the lipid bilayer system in the stratum corneum also contributing to the enhanced permeability of the epidermis.
  • the skin's permeability is increased by disruption of the intercellular lipids through a combination of heating and/or mechanical stress and through the increase in porosity.
  • Temperature rises to 50° C. (20 kHz, 10-30 W/cm 2 ) have been reported, but rises as little as 11° C. (1 MHz, 2 W/cm 2 ) have been shown to cause skin damage.
  • Continuous mode ultrasound at an intensity of 1 W/cm 2 raises the temperature of tissue at a depth of 3 cm to 40° C. in 10 minutes. It has been suggested that tissue must reach a temperature of 40-45° C. for at least 5 minutes to be therapeutically beneficial.
  • Tissue temperatures have been shown to increase at a rate of 0.860C/min when exposed to 1 W/cm 2 -1 MHz ultrasound.
  • Ultrasound is known to act to degrade polymers and has been used to increase in the release of incorporated drugs from these polymers.
  • compositions of the invention comprising polymers such as polysaccharides, preferably proteoglycans, in particular glucosaminoglycans, such as HA
  • the ultrasound will degrade (depolymerise) the polymer.
  • HA glucosaminoglycans
  • HA glucosaminoglycans
  • ultrasound generates shorter chain HA polymers that are more readily able to penetrate the skin.
  • it is important that the effective residence time of such actives at the site of action is maximised.
  • composition of the invention comprise polymers such as polysaccharides or proteoglycans, in particular glucosaminoglycans, such as HA
  • ultrasound treatment will assist in formation of a depot of the polymer (e.g. HA) within the skin which can act as a reservoir for slow release of actives providing an extended duration of effect.
  • Ultrasound also stimulates liberation of the active ingredients of the composition. Ultrasound will also act to depolymerise polymers polysaccharides or proteoglycans, in particular glucosaminoglycans, such as HA that have penetrated the skin. When HA and ascorbic acid are present in a composition, depolymerisation of the HA will be encouraged by ascorbic acid in which will react with atmospheric oxygen and stimulate depolymerisation.
  • a composition of the invention can be applied in conjunction with ultrasound, but this is not essential, a composition of the invention may also be applied to the skin without the application of ultrasound.
  • a first composition of the invention is applied in conjunction with ultrasound (either with an ultrasound pre-treatment of the skin to which the composition is applied, or with ultrasound treatment of skin during or after application of the composition to the skin) on a weekly, fortnightly or monthly basis.
  • a second composition of the invention may be applied, e.g. on a daily or 12 hourly basis without the need for ultrasound.
  • the first and second compositions can be identical or may differ in composition, but will both be compositions according to the invention.
  • the present invention further provides a dressing comprising a composition according to the invention, which may be presented in the form of a plaster, patch, gel patch bandage or foam.
  • kits comprising a composition according to the invention and optionally, a device comprising an ultrasound source and/or optionally an applicator for applying ultrasound to the skin and/or for applying the composition to the skin.
  • a kit according to the invention is suitable for performing a method of the invention as described herein.
  • a kit may further comprise instructions for use of the kit.
  • composition according to the invention provides the use of a composition according to the invention in the treatment of a cosmetic skin condition. Also provided is the use of composition according to the invention in the manufacture of a cosmetic composition for the treatment of a cosmetic skin condition e.g. selected from the group: scarring, sun damaged skin, ageing skin, wrinkles, coarseness, irregular pigmentation, telangiectasias, elastosis, cellulite, orange peel appearance of skin; dry skin conditions, scaliness, acne, stretch marks; rashes, chapping, inflamed skin; blemishes, rosacea, acne ice-pick scars, hypertrophic and keloid scars, and hairloss.
  • a cosmetic skin condition e.g. selected from the group: scarring, sun damaged skin, ageing skin, wrinkles, coarseness, irregular pigmentation, telangiectasias, elastosis, cellulite, orange peel appearance of skin; dry skin conditions, scaliness, acne, stretch marks; rashes
  • cosmetic skin conditions includes signs of skin ageing which include, but are not limited to, all outward visibly and tactilely perceptible manifestations as well as any other macro or micro effects due to skin ageing. Such signs may be induced or caused by intrinsic or extrinsic factors, e.g., chronological ageing and/or environmental damage (e.g., sunlight, UV, smoke, ozone, pollutants, stress, etc.).
  • signs of skin ageing include, but are not limited to, all outward visibly and tactilely perceptible manifestations as well as any other macro or micro effects due to skin ageing.
  • Such signs may be induced or caused by intrinsic or extrinsic factors, e.g., chronological ageing and/or environmental damage (e.g., sunlight, UV, smoke, ozone, pollutants, stress, etc.).
  • an acne lesion e.g., an acne lesion, in-grown hair, insect/spider bite or sting, scratch, cut, wound, abrasion, and the like
  • atrophy such as, but not limited to, that associated with ageing or steroid use; other histological or microscopic alterations in skin components such as ground substance (e.g., hyaluronic acid, glycosaminoglycans, etc.), collagen breakdown and structural alterations or abnormalities (e.g., changes in the stratum corneum, dermis, epidermis, the skin vascular system such as telangiectasia); tissue responses to insult such as itch or pruritus; and alterations to underlying tissues (e.g., subcutaneous fat, cellulite, muscles, trabeculae, septae, and the like), especially those proximate to the skin.
  • ground substance e.g., hyaluronic acid, glycosaminoglycans, etc.
  • the invention also provides the use of a composition according to the invention in a medical treatment or as a medicament.
  • a composition of the invention is provided for use as a medicament.
  • a composition according to the invention in the manufacture of a medicament for the treatment of a medical skin condition, e.g. selected from the group: scarring, sunburn, wounds, cuts, bruises, burns, burn scarring, eczema, dermatitis, dry skin conditions, urticaria, psoriasis.
  • FIG. 1 ( a )-( c ) show an array of transducer elements;
  • FIG. 1 ( d ) shows an individual transducer element with dual frequency capability.
  • FIG. 2 ( a )-( b ) show a transducer element.
  • FIG. 3A shows a single DDS chip for generation of alternative high and low frequencies, whereas in FIG. 3B high and low frequencies are generated in individual circuits.
  • FIG. 4 shows the effect of Topical 1 formulation on fibrillin expression proximal to the dermal-epidermal junction.
  • FIG. 5 shows the effect of Topical 1 formulation on MMP-1 expression in the epidermis.
  • FIG. 6 shows the of Topical 1 formulation on RAR ⁇ expression in the epidermis.
  • FIG. 7 shows the effect of Topical 1 formulation on HSP72 expression in the epidermis.
  • FIG. 8 shows the effect of Topical 1 formulation on fibrillin expression proximal to the dermal-epidermal junction following ultrasound treatment.
  • FIG. 9 shows the effect of Topical 1 formulation on epidermal MMP-1 expression following ultrasound treatment.
  • FIG. 10 shows the effect of Topical 1 formulation on epidermal HSP72 expression following ultrasound treatment.
  • FIG. 11 shows the effect of Topical 1 formulation on dermal clusterin expression following ultrasound treatment.
  • Topical Formulation “Topical 1”
  • Topical 1 is a composition according to the invention containing the following components: TABLE 3 Component Amount % w/w Hyaluronic acid (0.8-3 MDa mol wt range) 1% Hyaluronic acid (1.5-1.8 MDa mol wt range) 3% Ethanol 20% Ascorbic acid 3% Trisodium ascorbyl phosphate (STAY C-50) 1% Carnosine 3% N-Acetyl Carnosine 1% Arginine 3% Sterile distilled water to 100%
  • the standard four-day patch test assay was extended to a seven-day period to examine the effect of the Topical 1 formulation under occlusion or delivered by ultrasound on the induction of fibrillin expression as a mechanism by which clinical signs of photoageing may be improved.
  • t-RA made up in a vehicle comprising 67.2% ethanol 30% propylene glycol and 0.05% butyl hydroxytoluene (preservative) to 100% with deionised water (positive control),
  • Topical 1 was delivered with and without use of an ultrasound device.
  • Fibrillin is a major constituent of the elastin network in the papillary dermis and plays an important role in securing the epidermis to the underlying dermis.
  • Topical application of all-trans retinoic acid (t-RA) as a positive control ameliorates the clinical signs of photoageing.
  • t-RA all-trans retinoic acid
  • Ageing can also be monitored by examination of other molecules within the skin.
  • Previous work has identified alterations in the expression of the enzyme matrix metalloproteinase 1 (MMP-1; essential for extracellular matrix remodelling) 3 and in the nuclear retinoid receptor retinoic acid receptor a (RARa; necessary for modulating the effects of vitamin A and its derivatives) 4 .
  • MMP-1 matrix metalloproteinase 1
  • RARa nuclear retinoid receptor retinoic acid receptor a
  • Two molecular chaperones were assessed to identify pathways for eliminating abnormal proteins; these were heat shock protein-72 (HSP72) 5 and the extracellular chaperone, clustering.
  • Biopsies were embedded in OCT compound (Tissue-Tek®, Miles, Ind., USA) and snap frozen in liquid nitrogen. Biopsy sites were sutured with 1 ⁇ 4/o ethilon and subjects instructed to return between 7-10 days for suture removal.
  • Topical 1 formulation was applied to extensor forearms alone and with the aid of an ultrasound device (Duo SonTM unit, Orthosonics, Devon UK).
  • Low frequency (45 kHz, 100 mW/cm 2 , continuous) and high frequency (1 MHz, 1 W/cm 2 pulsed average, pulsed 20% cycle) were applied simultaneously for a period of ten minutes, during which time the ultrasound delivery head was moved over the skin.
  • Treatment occurred on days 1, 4 and 7 of the assay. On day 8, 3 mm punch biopsies were removed from each treatment site as described previously.
  • Frozen sections were prepared at a thickness of 10 ⁇ m (OTF cryostat, Bright Instruments Ltd.) and mounted onto gelatin-coated slides prior to histological analysis.
  • ECM extracellular matrix
  • the marker was identified in each of three sections (i.e., 3 sections/treatment/patient).
  • Sections were optimally fixed. Following hydration in tris-buffered saline (TBS; 100 mM Tris, 150 mM NaCl), sections were solublised by addition of 0.5% Triton®-X 100 (10 minutes). Following washing, endogenous peroxidase activity was abolished by incubation with an excess of hydrogen peroxide in methanol (30 minutes). Sections were blocked prior to application of primary antibody (overnight incubation at 4° C.). Negative controls were concurrently incubated with either block alone or control mouse serum. Following incubation, sections were stringently washed with TBS prior to application of an appropriate biotinylated secondary antibody.
  • TBS tris-buffered saline
  • the numbers of positive epidermal keratinocytes were assessed per high powered field, and the average score calculated for each site/test area.
  • MMP-1 staining was observed in both epidermis and dermis. There was a slight, non-significant, reduction in MMP-1 expression in epidermal keratinocytes following ultrasound treatment ( FIG. 9 ). TABLE 10 MMP-1 staining Treatment Mean Std Deviation Topical 114.71 22.03 Ultrasound 107.46 31.96 p > 0.05, non significant
  • HSP72 showed a slight, but non-significant, increase in epidermal expression following ultrasound treatment ( FIG. 10 ). TABLE 11 HSP72 staining Treatment Mean Std Deviation Topical 56.31 16.58 Ultrasound 67.57 16.41 p > 0.05, non significant
  • Clusterin also showed a slight, but non-significant, increase in dermal expression following ultrasound treatment ( FIG. 11 ). TABLE 12 Clusterin staining Treatment Mean Deviation Topical 1.80 0.98 Ultrasound 1.95 1.00 p > 0.05, non significant
  • Topical 1 formulation using an ultrasound device significantly increased fibrillin deposition proximal to the dermal-epidermal junction of photoaged skin.
  • HSP72 expression was modulated by both the Topical 1 formulation and all-trans RA. Furthermore, ultrasound delivery of Topical 1 formulation also resulted in increased HSP72 expression. It is possible that increased heat shock protein expression may be beneficial to the skin, by ‘priming’ cells to cope with environmental stressors (hormesis). Hence, increased HSP72 expression by epidermal keratinocytes may be involved in cellular repair processes following damage.
  • Topical 1 formulation applied with ultrasound appeared to induce a similar level of fibrillin to the retinoid formulation.
  • Topical 1 formulation only and Topical 1 formulation applied with ultrasound did not induce erythema or epidermal hyperplasia, unlike the retinoid formulation.
  • the degree of scarring at biopsy sites previously treated with ultrasound was noticeably lower than scarring at all other sites

Landscapes

  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Radiology & Medical Imaging (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Child & Adolescent Psychology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Media Introduction/Drainage Providing Device (AREA)
  • Surgical Instruments (AREA)
  • Percussion Or Vibration Massage (AREA)
US11/664,098 2004-10-11 2005-10-11 Apparatus for Treatment of Dermatological Conditions Abandoned US20080051680A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0422525.6A GB0422525D0 (en) 2004-10-11 2004-10-11 Dermatological compositions and methods
GB0422525.6 2004-10-11
PCT/GB2005/050181 WO2006040597A1 (en) 2004-10-11 2005-10-11 Apparatus for treatment of dermatological conditions

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2005/050181 A-371-Of-International WO2006040597A1 (en) 2004-10-11 2005-10-11 Apparatus for treatment of dermatological conditions

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/137,043 Division US10406383B2 (en) 2004-10-11 2011-07-18 Apparatus for treatment of dermatological conditions

Publications (1)

Publication Number Publication Date
US20080051680A1 true US20080051680A1 (en) 2008-02-28

Family

ID=33443702

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/664,098 Abandoned US20080051680A1 (en) 2004-10-11 2005-10-11 Apparatus for Treatment of Dermatological Conditions
US13/137,043 Active 2028-05-07 US10406383B2 (en) 2004-10-11 2011-07-18 Apparatus for treatment of dermatological conditions

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/137,043 Active 2028-05-07 US10406383B2 (en) 2004-10-11 2011-07-18 Apparatus for treatment of dermatological conditions

Country Status (11)

Country Link
US (2) US20080051680A1 (ja)
EP (2) EP1812110B1 (ja)
JP (3) JP5268361B2 (ja)
KR (1) KR101173716B1 (ja)
CN (2) CN101102815B (ja)
CA (1) CA2582787C (ja)
DK (2) DK1812110T3 (ja)
ES (1) ES2427426T3 (ja)
GB (1) GB0422525D0 (ja)
RU (1) RU2388504C2 (ja)
WO (1) WO2006040597A1 (ja)

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090149923A1 (en) * 2007-12-07 2009-06-11 21X Corporation Dba Priavision, Inc. Method for equi-dosed time fractionated pulsed uva irradiation of collagen/riboflavin mixtures for ocular structural augmentation
US7607347B2 (en) * 2006-03-07 2009-10-27 Gems Sensors, Inc. Fluid level detector
US20100003664A1 (en) * 2008-07-01 2010-01-07 Lou Reinisch System for Glycated Protein Detection
US20100004536A1 (en) * 2008-07-03 2010-01-07 Avner Rosenberg Method and apparatus for ultrasound tissue treatment
US20100016849A1 (en) * 2008-07-16 2010-01-21 Avner Rosenberg Rf electrode for aesthetic and body shaping devices and method of using same
US20100016761A1 (en) * 2008-07-16 2010-01-21 Avner Rosenberg Applicator for skin treatement with automatic regulation of skin protrusion magnitude
US20100152626A1 (en) * 2006-08-22 2010-06-17 Schwartz Donald N Ultrasonic treatment of glaucoma
US20100294034A1 (en) * 2005-01-10 2010-11-25 Gems Sensors, Inc. Fluid level detector
US20110105961A1 (en) * 2008-05-23 2011-05-05 Gruber Lewis S Methods, compositions and apparatuses for facilitating regeneration
US20110137386A1 (en) * 2004-09-01 2011-06-09 Michael Kreindel Method and system for invasive skin treatment
WO2011078905A1 (en) * 2009-12-22 2011-06-30 Avon Products, Inc. Coupling emulsions for use with ultrasound devices
US20120089052A1 (en) * 2010-10-12 2012-04-12 Yuchen Zhou Massaging device with multiple ultrasonic transducers
WO2012067887A3 (en) * 2010-11-15 2012-07-19 National Health Research Institutes Multiple-frequency ultrasonic phased array driving system
US9061128B2 (en) 2013-03-15 2015-06-23 Sonovia Holdings Llc Light and/or ultrasonic transducer device with sensor feedback for dose control
WO2015153620A1 (en) * 2014-04-01 2015-10-08 Dermal Photonics Corporation Systems and methods for treating dermatological imperfections
US9278230B2 (en) 2009-02-25 2016-03-08 Syneron Medical Ltd Electrical skin rejuvenation
US9295607B2 (en) 2009-08-20 2016-03-29 Syneron Medical Ltd Method and apparatus for non-invasive aesthetic treatment of skin and sub-dermis
US9320919B2 (en) 2010-11-22 2016-04-26 Siwa Corporation Selective removal of cells having accumulated agents
US9326910B2 (en) 2012-01-11 2016-05-03 Syneron Medical Ltd Large area body shaping applicator
US9474676B2 (en) 2004-09-20 2016-10-25 P Tech, Llc Acoustic therapy device
US9492687B2 (en) 2009-12-31 2016-11-15 ZetrOZ Systems, LLC Low-profile ultrasound transducer
US9649376B2 (en) 2010-09-27 2017-05-16 Siwa Corporation Selective removal of age-modified cells for treatment of atherosclerosis
US9993535B2 (en) 2014-12-18 2018-06-12 Siwa Corporation Method and composition for treating sarcopenia
KR101873888B1 (ko) * 2015-09-30 2018-07-04 (주)아모레퍼시픽 초음파 조사 기기 및 초음파 조사 방법
US10206813B2 (en) 2009-05-18 2019-02-19 Dose Medical Corporation Implants with controlled drug delivery features and methods of using same
US10245178B1 (en) 2011-06-07 2019-04-02 Glaukos Corporation Anterior chamber drug-eluting ocular implant
US10358502B2 (en) 2014-12-18 2019-07-23 Siwa Corporation Product and method for treating sarcopenia
US10406383B2 (en) 2004-10-11 2019-09-10 Carewear Corp. Apparatus for treatment of dermatological conditions
US10406029B2 (en) 2001-04-07 2019-09-10 Glaukos Corporation Ocular system with anchoring implant and therapeutic agent
US10584180B2 (en) 2014-09-19 2020-03-10 Siwa Corporation Anti-AGE antibodies for treating inflammation and auto-immune disorders
US10639498B2 (en) 2016-05-26 2020-05-05 Carewear Corp. Photoeradication of microorganisms with pulsed purple or blue light
US10695582B2 (en) 2012-09-10 2020-06-30 Dermal Photonics Corporation Systems and methods for treating dermatological imperfections
WO2020223242A1 (en) * 2019-05-01 2020-11-05 Mechanobiologics Llc Systems and methods for cancer treatment
WO2020223359A1 (en) * 2019-04-30 2020-11-05 Mechanobiologics Llc Systems and methods for immersion mechanotherapy
US10858449B1 (en) 2017-01-06 2020-12-08 Siwa Corporation Methods and compositions for treating osteoarthritis
US10919957B2 (en) 2017-04-13 2021-02-16 Siwa Corporation Humanized monoclonal advanced glycation end-product antibody
US10925937B1 (en) 2017-01-06 2021-02-23 Siwa Corporation Vaccines for use in treating juvenile disorders associated with inflammation
US10961321B1 (en) 2017-01-06 2021-03-30 Siwa Corporation Methods and compositions for treating pain associated with inflammation
US10959941B2 (en) 2014-05-29 2021-03-30 Glaukos Corporation Implants with controlled drug delivery features and methods of using same
US10995151B1 (en) 2017-01-06 2021-05-04 Siwa Corporation Methods and compositions for treating disease-related cachexia
US11020605B2 (en) 2018-05-29 2021-06-01 Carewear Corp. Method and system for irradiating tissue with pulsed blue and red light to reduce muscle fatigue, enhance wound healing and tissue repair, and reduce pain
US20210236861A1 (en) * 2018-10-08 2021-08-05 Su Gun LEE Portable ultrasonic stimulator
US11202749B2 (en) 2017-03-06 2021-12-21 Haplnscience inc. Composition for skin aging measurement, prevention, or alleviation, using HAPLN1
US11213585B2 (en) 2016-06-23 2022-01-04 Siwa Corporation Vaccines for use in treating various diseases and disorders
US11318043B2 (en) 2016-04-20 2022-05-03 Dose Medical Corporation Bioresorbable ocular drug delivery device
US11518801B1 (en) 2017-12-22 2022-12-06 Siwa Corporation Methods and compositions for treating diabetes and diabetic complications
US11564833B2 (en) 2015-09-25 2023-01-31 Glaukos Corporation Punctal implants with controlled drug delivery features and methods of using same
US11833202B2 (en) 2016-02-19 2023-12-05 Siwa Corporation Method and composition for treating cancer, killing metastatic cancer cells and preventing cancer metastasis using antibody to advanced glycation end products (AGE)
US11925578B2 (en) 2015-09-02 2024-03-12 Glaukos Corporation Drug delivery implants with bi-directional delivery capacity
US11958900B2 (en) 2016-04-15 2024-04-16 Siwa Corporation Anti-age antibodies for treating neurodegenerative disorders

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10864385B2 (en) 2004-09-24 2020-12-15 Guided Therapy Systems, Llc Rejuvenating skin by heating tissue for cosmetic treatment of the face and body
US8535228B2 (en) 2004-10-06 2013-09-17 Guided Therapy Systems, Llc Method and system for noninvasive face lifts and deep tissue tightening
US8444562B2 (en) 2004-10-06 2013-05-21 Guided Therapy Systems, Llc System and method for treating muscle, tendon, ligament and cartilage tissue
US8690778B2 (en) 2004-10-06 2014-04-08 Guided Therapy Systems, Llc Energy-based tissue tightening
US11235179B2 (en) 2004-10-06 2022-02-01 Guided Therapy Systems, Llc Energy based skin gland treatment
US9694212B2 (en) 2004-10-06 2017-07-04 Guided Therapy Systems, Llc Method and system for ultrasound treatment of skin
US11883688B2 (en) 2004-10-06 2024-01-30 Guided Therapy Systems, Llc Energy based fat reduction
US8133180B2 (en) 2004-10-06 2012-03-13 Guided Therapy Systems, L.L.C. Method and system for treating cellulite
US11724133B2 (en) 2004-10-07 2023-08-15 Guided Therapy Systems, Llc Ultrasound probe for treatment of skin
US11207548B2 (en) 2004-10-07 2021-12-28 Guided Therapy Systems, L.L.C. Ultrasound probe for treating skin laxity
FR2899487A1 (fr) * 2006-04-10 2007-10-12 Galderma Res & Dev Application d'ultrasons aux ongles
JPWO2009136587A1 (ja) * 2008-05-08 2011-09-08 株式会社カネカ 抗疲労組成物
JP5619733B2 (ja) 2008-06-06 2014-11-05 ウルセラ インコーポレイテッド 美的処置システム
WO2010075547A2 (en) 2008-12-24 2010-07-01 Guided Therapy Systems, Llc Methods and systems for fat reduction and/or cellulite treatment
EP2263808B8 (en) 2009-06-19 2014-04-30 Sonovia Holdings LLC Dual-Frequency Ultrasound Transducer
KR101140792B1 (ko) * 2009-10-07 2012-05-03 주식회사 노블테크 다중 채널 정현파 발생 장치를 이용한 치료 시스템
ES2358829B1 (es) * 2009-10-23 2012-06-25 Lipotec, S.A. Péptidos útiles en el tratamiento y/o cuidado de la piel, mucosas y/o cabello y su uso en composiciones cosméticas o farmacéuticas.
WO2011148314A1 (en) * 2010-05-27 2011-12-01 Koninklijke Philips Electronics N.V. Ultrasound transducer for selectively generating ultrasound waves and heat
JP2012081272A (ja) * 2010-10-12 2012-04-26 La Pierres Inc 複数の超音波のトランスデューサーを持ったマッサージ装置関連出願の援用本出願は、２０１０年１０月１２日に提出された仮出願第６１／４０４，９２３号への優先権を主張し、そしてその全体の内容はこれによって援用のために合体させられる。
DE102011016522A1 (de) * 2011-04-08 2012-10-11 SE-DA medical group SE Multifunktionsmaske
WO2013033066A1 (en) * 2011-09-02 2013-03-07 Drexel University Ultrasound device and therapeutic methods
US9474685B2 (en) 2011-09-28 2016-10-25 Sure-Shot Medical Device Inc. Apparatus for localized dermatological treatment
RU2495928C2 (ru) 2012-01-30 2013-10-20 Сергей Юрьевич Лешков Средство для стимуляции синтеза белков теплового шока hsp 70 в клетках человека и животных; косметическое средство для стимуляции репаративных процессов; косметическое средство для снижения побочных эффектов агрессивных косметологических процедур; биологически активная добавка; пищевой продукт; способ снижения побочных эффектов агрессивных косметологических процедур
US20140066837A1 (en) 2012-07-26 2014-03-06 Ronald L. Moy Skin care compositions and methods
JP2014162748A (ja) * 2013-02-25 2014-09-08 Kagawa Univ 皮膚の光老化抑制剤
CN113648552A (zh) 2013-03-08 2021-11-16 奥赛拉公司 用于多焦点超声治疗的装置和方法
ES2899159T3 (es) * 2013-06-24 2022-03-10 Zetroz Systems Llc Dispositivo portátil de ultrasonido
US11432990B2 (en) 2013-08-30 2022-09-06 ISOS Solutions, LLC Textured apparatus with therapeutic material incorporated therein and methods of manufacturing same
WO2015077006A1 (en) * 2013-11-22 2015-05-28 Sonify Biosciences, Llc Skin cancer treatment using low intensity ultrasound
US20150174387A1 (en) * 2013-12-23 2015-06-25 L'oreal Combined sonic and ultrasonic skin care device
CN103961276A (zh) * 2014-01-08 2014-08-06 片仔癀（上海）生物科技研发有限公司 抗糖化化妆品组合物及含其的抗糖化化妆品
KR102465947B1 (ko) 2014-04-18 2022-11-10 얼테라, 인크 밴드 트랜스듀서 초음파 치료
FR3023164B1 (fr) * 2014-07-03 2017-10-20 Expanscience Lab Extraits peptidiques de lupin et fermete de la peau
WO2016122752A1 (en) * 2015-01-28 2016-08-04 Ojai Retinal Technology, Llc Pulsating electromagnetic and ultrasound therapy for stimulating targeted heat shock proteins and facilitating protein repair
ES2796330T3 (es) * 2015-07-29 2020-11-26 Koninklijke Philips Nv Estimulación del crecimiento del pelo
WO2017079760A1 (en) * 2015-11-06 2017-05-11 Bkr Ip Holdco Llc Method for glucose control in diabetics
RU2720661C2 (ru) 2016-01-18 2020-05-12 Ультера, Инк. Компактное ультразвуковое устройство, содержащее кольцеобразную ультразвуковую матрицу, электрически соединенную по периферии с гибкой печатной платой, и способ сборки такого устройства
JP6782075B2 (ja) * 2016-01-19 2020-11-11 ロート製薬株式会社 コラーゲンリモデリング剤およびそれを用いた皮膚外用剤、飲食品、並びに美容方法。
JP6782074B2 (ja) * 2016-01-19 2020-11-11 ロート製薬株式会社 ルミカン産生促進剤およびそれを用いた皮膚外用剤、飲食品、並びに美容方法。
CN105726518A (zh) * 2016-02-26 2016-07-06 深圳杉源医疗科技有限公司 一种肌肤内无创导入玻尿酸的方法
RU2639805C2 (ru) * 2016-04-04 2017-12-22 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московская государственная академия ветеринарной медицины и биотехнологии - МВА имени К.И. Скрябина" (ФГБОУ ВО МГАВМиБ - МВА имени К.И. Скрябина) Способ направленного неинвазивного воздействия на морфологическое состояние клеток-мишеней тканей представителей семейства кошачьих
JP6004360B1 (ja) * 2016-05-16 2016-10-05 有限会社上山製作所 腹部用マッサージ装置
SG11201809850QA (en) 2016-08-16 2018-12-28 Ulthera Inc Systems and methods for cosmetic ultrasound treatment of skin
WO2019164836A1 (en) 2018-02-20 2019-08-29 Ulthera, Inc. Systems and methods for combined cosmetic treatment of cellulite with ultrasound
KR102436432B1 (ko) * 2018-10-08 2022-10-14 주식회사 투앤파트너스 휴대용 초음파 자극기
KR20200132478A (ko) * 2019-05-17 2020-11-25 엘지이노텍 주식회사 마스크 및 이를 포함하는 피부 관리 기기
LT6788B (lt) 2019-05-22 2020-12-28 Vilniaus Gedimino technikos universitetas Orlaivio vairas su dvigubu vyriu
CN110732098A (zh) * 2019-10-22 2020-01-31 珠海泓韵科技有限公司 美容仪及其美容方法
CN110787379A (zh) * 2019-11-08 2020-02-14 昆明医科大学 一种黑色素治疗系统
WO2021098887A1 (zh) 2019-11-21 2021-05-27 上海市第六人民医院 可穿戴柔性超声尿道瘢痕治疗仪
CN111265788A (zh) * 2020-02-18 2020-06-12 清华大学 用于超声波治疗的柔性超声波器件及其制备方法
JP2023516924A (ja) * 2020-02-24 2023-04-21 ビー．ジー． ネゲヴ テクノロジーズ アンド アプリケーションズ リミテッド、アット ベン－グリオン ユニヴァーシティ グリコサミノグリカン（ｇａｇ）の経皮送達を増強するための方法
US20220062147A1 (en) * 2020-09-03 2022-03-03 Bottled Science Limited Skin Care Formulation for Treatment of Cellulite
EP4392011A1 (en) * 2022-06-03 2024-07-03 Colgate-Palmolive Company Skin care compositions and methods of use

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4767402A (en) * 1986-07-08 1988-08-30 Massachusetts Institute Of Technology Ultrasound enhancement of transdermal drug delivery
US5186162A (en) * 1988-09-14 1993-02-16 Interpore Orthopaedics, Inc. Ultrasonic transducer device for treatment of living tissue and/or cells
US5507790A (en) * 1994-03-21 1996-04-16 Weiss; William V. Method of non-invasive reduction of human site-specific subcutaneous fat tissue deposits by accelerated lipolysis metabolism
US5665053A (en) * 1996-09-27 1997-09-09 Jacobs; Robert A. Apparatus for performing endermology with ultrasound
US6030374A (en) * 1998-05-29 2000-02-29 Mcdaniel; David H. Ultrasound enhancement of percutaneous drug absorption
US6113559A (en) * 1997-12-29 2000-09-05 Klopotek; Peter J. Method and apparatus for therapeutic treatment of skin with ultrasound
US6200266B1 (en) * 1998-03-31 2001-03-13 Case Western Reserve University Method and apparatus for ultrasound imaging using acoustic impedance reconstruction
US20030055337A1 (en) * 2001-09-14 2003-03-20 Lin Gregory Sharat Dual-frequency ultrasonic array transducer and method of harmonic imaging
US6565520B1 (en) * 1996-08-23 2003-05-20 Orthosonics Ltd. Apparatus for ultrasonic therapeutic treatment
US6613005B1 (en) * 2000-11-28 2003-09-02 Insightec-Txsonics, Ltd. Systems and methods for steering a focused ultrasound array
US20050043654A1 (en) * 2002-01-21 2005-02-24 Yuko Matsumura Ultrasonic percutaneous permeating device, ultrasonic percutaneous permeating kit, and ultrasonic percutaneous permeating method

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5115805A (en) * 1990-02-23 1992-05-26 Cygnus Therapeutic Systems Ultrasound-enhanced delivery of materials into and through the skin
JP3102655B2 (ja) * 1991-12-27 2000-10-23 住友製薬株式会社 超音波制御による薬物放出製剤
CN1082406A (zh) 1992-12-13 1994-02-23 张文琦 复方维甲酸油
JPH06312023A (ja) * 1993-04-28 1994-11-08 Meiji Seika Kaisha Ltd 角質層内搬送用具
GB9408668D0 (en) * 1994-04-30 1994-06-22 Orthosonics Ltd Untrasonic therapeutic system
IT1274590B (it) * 1994-08-05 1997-07-18 Ambrogio Lazzari Apparecchiatura multifunzionale per trattamenti estetici
GB2303552A (en) 1995-07-24 1997-02-26 Gar Investment Corp Ultrasound apparatus for non invasive cellulite reduction
US5618275A (en) * 1995-10-27 1997-04-08 Sonex International Corporation Ultrasonic method and apparatus for cosmetic and dermatological applications
CN2246523Y (zh) 1996-02-01 1997-02-05 江山 平面铲形超声波美容仪探头
EP0925088A2 (en) 1996-06-28 1999-06-30 Sontra Medical, L.P. Ultrasound enhancement of transdermal transport
FR2779059B1 (fr) * 1998-05-29 2004-09-10 Guerlain Procede de traitement cosmetique pour lutter contre les effets du vieillissement cutane; nouvelles compositions cosmetiques pour sa mise en oeuvre
IL119827A (en) 1996-12-13 2001-08-08 Technion Res & Dev Foundation Method and device for inserting materials in ultrasound
US6585763B1 (en) * 1997-10-14 2003-07-01 Vascusense, Inc. Implantable therapeutic device and method
US6190315B1 (en) 1998-01-08 2001-02-20 Sontra Medical, Inc. Sonophoretic enhanced transdermal transport
US6120454A (en) 1998-02-03 2000-09-19 Boston Scientific Corporation Annular array ultrasound catheter
WO1999048621A2 (en) 1998-03-26 1999-09-30 Exogen, Inc. Arrays made from flexible transducer elements
AU763551B2 (en) 1998-05-06 2003-07-24 Exogen, Inc. Ultrasound bandages
US20040171980A1 (en) 1998-12-18 2004-09-02 Sontra Medical, Inc. Method and apparatus for enhancement of transdermal transport
JP2001115197A (ja) * 1999-10-14 2001-04-24 Take:Kk 石 鹸
US6692773B2 (en) * 2000-07-27 2004-02-17 Nucryst Pharmaceuticals Corp. Treatment of hyperproliferative skin disorders and diseases
US7273457B2 (en) 2000-10-16 2007-09-25 Remon Medical Technologies, Ltd. Barometric pressure correction based on remote sources of information
US7527806B2 (en) * 2002-04-26 2009-05-05 Unilever Home & Personal Care Usa Division Of Conopco, Inc. Personal care article with distinct active zone
FR2844715B1 (fr) * 2002-09-20 2007-04-27 Af Consulting Composition pour des soins de la peau, et contenant un ou des oligomeres de resveratrol, en particulier de l'epsilone-viniferine, et ou certains de leurs derives
EP1599142A2 (en) * 2003-02-19 2005-11-30 Second Stage Ventures, Inc. Method and apparatus for transdermal drug delivery device
US20040175347A1 (en) 2003-03-04 2004-09-09 The Procter & Gamble Company Regulation of mammalian keratinous tissue using hexamidine compositions
US20040267129A1 (en) * 2003-05-30 2004-12-30 Angelsen Bjorn A.J. Ultrasonic contrast agent detection and imaging by low frequency manipulation of high frequency scattering properties
US20050154314A1 (en) * 2003-12-30 2005-07-14 Liposonix, Inc. Component ultrasound transducer
GB0422525D0 (en) 2004-10-11 2004-11-10 Luebcke Peter Dermatological compositions and methods
US7727156B2 (en) * 2005-07-26 2010-06-01 Angelsen Bjoern A J Dual frequency band ultrasound transducer arrays
EP2821103B1 (en) 2008-07-14 2019-05-15 Arizona Board Regents For And On Behalf Of Arizona State University Devices for modulating cellular activity using ultrasound
US20110071482A1 (en) 2009-01-28 2011-03-24 Selevan James R Devices and methods for signaling when action is due in relation to a medical device

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4767402A (en) * 1986-07-08 1988-08-30 Massachusetts Institute Of Technology Ultrasound enhancement of transdermal drug delivery
US5186162A (en) * 1988-09-14 1993-02-16 Interpore Orthopaedics, Inc. Ultrasonic transducer device for treatment of living tissue and/or cells
US5507790A (en) * 1994-03-21 1996-04-16 Weiss; William V. Method of non-invasive reduction of human site-specific subcutaneous fat tissue deposits by accelerated lipolysis metabolism
US6565520B1 (en) * 1996-08-23 2003-05-20 Orthosonics Ltd. Apparatus for ultrasonic therapeutic treatment
US5665053A (en) * 1996-09-27 1997-09-09 Jacobs; Robert A. Apparatus for performing endermology with ultrasound
US6113559A (en) * 1997-12-29 2000-09-05 Klopotek; Peter J. Method and apparatus for therapeutic treatment of skin with ultrasound
US6200266B1 (en) * 1998-03-31 2001-03-13 Case Western Reserve University Method and apparatus for ultrasound imaging using acoustic impedance reconstruction
US6030374A (en) * 1998-05-29 2000-02-29 Mcdaniel; David H. Ultrasound enhancement of percutaneous drug absorption
US6613005B1 (en) * 2000-11-28 2003-09-02 Insightec-Txsonics, Ltd. Systems and methods for steering a focused ultrasound array
US20030055337A1 (en) * 2001-09-14 2003-03-20 Lin Gregory Sharat Dual-frequency ultrasonic array transducer and method of harmonic imaging
US20050043654A1 (en) * 2002-01-21 2005-02-24 Yuko Matsumura Ultrasonic percutaneous permeating device, ultrasonic percutaneous permeating kit, and ultrasonic percutaneous permeating method

Cited By (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10406029B2 (en) 2001-04-07 2019-09-10 Glaukos Corporation Ocular system with anchoring implant and therapeutic agent
US8906015B2 (en) 2004-09-01 2014-12-09 Syneron Medical, Ltd Method and system for invasive skin treatment
US20110137386A1 (en) * 2004-09-01 2011-06-09 Michael Kreindel Method and system for invasive skin treatment
US8900231B2 (en) 2004-09-01 2014-12-02 Syneron Medical Ltd Method and system for invasive skin treatment
US11534187B2 (en) 2004-09-20 2022-12-27 P Tech, Llc Acoustic therapy device
US10639052B2 (en) 2004-09-20 2020-05-05 P Tech, Llc Acoustic therapy device
US9474676B2 (en) 2004-09-20 2016-10-25 P Tech, Llc Acoustic therapy device
US10406383B2 (en) 2004-10-11 2019-09-10 Carewear Corp. Apparatus for treatment of dermatological conditions
US8850883B2 (en) 2005-01-10 2014-10-07 Gems Sensors, Inc. Fluid level detector
US20100294034A1 (en) * 2005-01-10 2010-11-25 Gems Sensors, Inc. Fluid level detector
US7946169B2 (en) 2006-03-07 2011-05-24 Gems Sensors, Inc. Fluid level detector
US9631968B2 (en) 2006-03-07 2017-04-25 Gems Sensors, Inc. Fluid level detector
US20110219871A1 (en) * 2006-03-07 2011-09-15 Gems Sensors, Inc. Fluid level detector
US7607347B2 (en) * 2006-03-07 2009-10-27 Gems Sensors, Inc. Fluid level detector
US8813558B2 (en) 2006-03-07 2014-08-26 Gems Sensors, Inc. Fluid level detector
US20100005878A1 (en) * 2006-03-07 2010-01-14 Gems Sensors, Inc. Fluid level detector
US8043235B2 (en) * 2006-08-22 2011-10-25 Schwartz Donald N Ultrasonic treatment of glaucoma
US20100152626A1 (en) * 2006-08-22 2010-06-17 Schwartz Donald N Ultrasonic treatment of glaucoma
US20090149923A1 (en) * 2007-12-07 2009-06-11 21X Corporation Dba Priavision, Inc. Method for equi-dosed time fractionated pulsed uva irradiation of collagen/riboflavin mixtures for ocular structural augmentation
US20110105961A1 (en) * 2008-05-23 2011-05-05 Gruber Lewis S Methods, compositions and apparatuses for facilitating regeneration
US20180044411A1 (en) * 2008-05-23 2018-02-15 Siwa Corporation Methods, compositions and apparatuses for facilitating regeneration
KR101592156B1 (ko) * 2008-05-23 2016-02-04 시와 코퍼레이션 재생을 촉진하는 방법, 조성물 및 장치
US9161810B2 (en) 2008-05-23 2015-10-20 Siwa Corporation Methods, compositions and apparatuses for facilitating regeneration
US11261241B2 (en) * 2008-05-23 2022-03-01 Siwa Corporation Methods, compositions and apparatuses for facilitating regeneration
US20100003664A1 (en) * 2008-07-01 2010-01-07 Lou Reinisch System for Glycated Protein Detection
US20100004536A1 (en) * 2008-07-03 2010-01-07 Avner Rosenberg Method and apparatus for ultrasound tissue treatment
US9314293B2 (en) 2008-07-16 2016-04-19 Syneron Medical Ltd RF electrode for aesthetic and body shaping devices and method of using same
US20120197242A1 (en) * 2008-07-16 2012-08-02 Avner Rosenberg Applicator for skin treatement with automatic regulation of skin protrusion magnitude
US9333377B2 (en) * 2008-07-16 2016-05-10 Syneron Medical Ltd Applicator for skin treatement with automatic regulation of skin protrusion magnitude
US20100016761A1 (en) * 2008-07-16 2010-01-21 Avner Rosenberg Applicator for skin treatement with automatic regulation of skin protrusion magnitude
US20100016849A1 (en) * 2008-07-16 2010-01-21 Avner Rosenberg Rf electrode for aesthetic and body shaping devices and method of using same
US9295858B2 (en) * 2008-07-16 2016-03-29 Syneron Medical, Ltd Applicator for skin treatment with automatic regulation of skin protrusion magnitude
US9278230B2 (en) 2009-02-25 2016-03-08 Syneron Medical Ltd Electrical skin rejuvenation
US11426306B2 (en) 2009-05-18 2022-08-30 Dose Medical Corporation Implants with controlled drug delivery features and methods of using same
US10206813B2 (en) 2009-05-18 2019-02-19 Dose Medical Corporation Implants with controlled drug delivery features and methods of using same
US9295607B2 (en) 2009-08-20 2016-03-29 Syneron Medical Ltd Method and apparatus for non-invasive aesthetic treatment of skin and sub-dermis
EP2515772A4 (en) * 2009-12-22 2017-02-08 Avon Products, Inc. Coupling emulsions for use with ultrasound devices
WO2011078905A1 (en) * 2009-12-22 2011-06-30 Avon Products, Inc. Coupling emulsions for use with ultrasound devices
US20120259252A1 (en) * 2009-12-22 2012-10-11 Avon Products, Inc. Coupling Emulsions for Use With Ultrasound Devices
US9492687B2 (en) 2009-12-31 2016-11-15 ZetrOZ Systems, LLC Low-profile ultrasound transducer
US10226531B2 (en) 2010-09-27 2019-03-12 Siwa Corporation Selective removal of age-modified cells for treatment of atherosclerosis
US9649376B2 (en) 2010-09-27 2017-05-16 Siwa Corporation Selective removal of age-modified cells for treatment of atherosclerosis
US20120089052A1 (en) * 2010-10-12 2012-04-12 Yuchen Zhou Massaging device with multiple ultrasonic transducers
WO2012067887A3 (en) * 2010-11-15 2012-07-19 National Health Research Institutes Multiple-frequency ultrasonic phased array driving system
TWI426245B (zh) * 2010-11-15 2014-02-11 Nat Health Research Institutes 複頻超音波相位陣列驅動系統
US8485974B2 (en) 2010-11-15 2013-07-16 National Health Research Institutes Multiple-frequency ultrasonic phased array driving system
US10960234B2 (en) 2010-11-22 2021-03-30 Siwa Corporation Selective removal of cells having accumulated agents
US9320919B2 (en) 2010-11-22 2016-04-26 Siwa Corporation Selective removal of cells having accumulated agents
US10245178B1 (en) 2011-06-07 2019-04-02 Glaukos Corporation Anterior chamber drug-eluting ocular implant
US9326910B2 (en) 2012-01-11 2016-05-03 Syneron Medical Ltd Large area body shaping applicator
US10561570B2 (en) 2012-01-11 2020-02-18 Syneron Medical Ltd. Large area body shaping applicator
US10695582B2 (en) 2012-09-10 2020-06-30 Dermal Photonics Corporation Systems and methods for treating dermatological imperfections
EP3446743A1 (en) 2013-03-15 2019-02-27 Carewear Corp. Ultrasonic transducer device
US9061128B2 (en) 2013-03-15 2015-06-23 Sonovia Holdings Llc Light and/or ultrasonic transducer device with sensor feedback for dose control
KR101975635B1 (ko) 2013-03-15 2019-05-07 케어웨어 코프. 광 및 초음파 트랜스듀서 장치
KR20150135335A (ko) * 2013-03-15 2015-12-02 소노비아 홀딩스 엘엘씨 광 및 초음파 트랜스듀서 장치
US11253394B2 (en) 2013-03-15 2022-02-22 Dose Medical Corporation Controlled drug delivery ocular implants and methods of using same
US11083619B2 (en) 2013-03-15 2021-08-10 Carewear Corp. Organic LED light and ultrasonic transducer device in a flexible layer configuration with electrical stimulation
US9561357B2 (en) 2013-03-15 2017-02-07 Sonovia Holdings Llc Light and ultrasonic transducer device for skin therapy
EP3446742A1 (en) 2013-03-15 2019-02-27 Carewear Corp. Light therapy device
WO2015153620A1 (en) * 2014-04-01 2015-10-08 Dermal Photonics Corporation Systems and methods for treating dermatological imperfections
US10959941B2 (en) 2014-05-29 2021-03-30 Glaukos Corporation Implants with controlled drug delivery features and methods of using same
US11992551B2 (en) 2014-05-29 2024-05-28 Glaukos Corporation Implants with controlled drug delivery features and methods of using same
US10584180B2 (en) 2014-09-19 2020-03-10 Siwa Corporation Anti-AGE antibodies for treating inflammation and auto-immune disorders
US10358502B2 (en) 2014-12-18 2019-07-23 Siwa Corporation Product and method for treating sarcopenia
US11872269B2 (en) 2014-12-18 2024-01-16 Siwa Corporation Method and composition for treating sarcopenia
US11873345B2 (en) 2014-12-18 2024-01-16 Siwa Corporation Product and method for treating sarcopenia
US9993535B2 (en) 2014-12-18 2018-06-12 Siwa Corporation Method and composition for treating sarcopenia
US11925578B2 (en) 2015-09-02 2024-03-12 Glaukos Corporation Drug delivery implants with bi-directional delivery capacity
US11564833B2 (en) 2015-09-25 2023-01-31 Glaukos Corporation Punctal implants with controlled drug delivery features and methods of using same
KR101873888B1 (ko) * 2015-09-30 2018-07-04 (주)아모레퍼시픽 초음파 조사 기기 및 초음파 조사 방법
US11833202B2 (en) 2016-02-19 2023-12-05 Siwa Corporation Method and composition for treating cancer, killing metastatic cancer cells and preventing cancer metastasis using antibody to advanced glycation end products (AGE)
US11958900B2 (en) 2016-04-15 2024-04-16 Siwa Corporation Anti-age antibodies for treating neurodegenerative disorders
US11318043B2 (en) 2016-04-20 2022-05-03 Dose Medical Corporation Bioresorbable ocular drug delivery device
US10639498B2 (en) 2016-05-26 2020-05-05 Carewear Corp. Photoeradication of microorganisms with pulsed purple or blue light
US11213585B2 (en) 2016-06-23 2022-01-04 Siwa Corporation Vaccines for use in treating various diseases and disorders
US10995151B1 (en) 2017-01-06 2021-05-04 Siwa Corporation Methods and compositions for treating disease-related cachexia
US10858449B1 (en) 2017-01-06 2020-12-08 Siwa Corporation Methods and compositions for treating osteoarthritis
US10961321B1 (en) 2017-01-06 2021-03-30 Siwa Corporation Methods and compositions for treating pain associated with inflammation
US10925937B1 (en) 2017-01-06 2021-02-23 Siwa Corporation Vaccines for use in treating juvenile disorders associated with inflammation
US11202749B2 (en) 2017-03-06 2021-12-21 Haplnscience inc. Composition for skin aging measurement, prevention, or alleviation, using HAPLN1
US11542324B2 (en) 2017-04-13 2023-01-03 Siwa Corporation Humanized monoclonal advanced glycation end-product antibody
US10919957B2 (en) 2017-04-13 2021-02-16 Siwa Corporation Humanized monoclonal advanced glycation end-product antibody
US11518801B1 (en) 2017-12-22 2022-12-06 Siwa Corporation Methods and compositions for treating diabetes and diabetic complications
US11020605B2 (en) 2018-05-29 2021-06-01 Carewear Corp. Method and system for irradiating tissue with pulsed blue and red light to reduce muscle fatigue, enhance wound healing and tissue repair, and reduce pain
US20210236861A1 (en) * 2018-10-08 2021-08-05 Su Gun LEE Portable ultrasonic stimulator
WO2020223359A1 (en) * 2019-04-30 2020-11-05 Mechanobiologics Llc Systems and methods for immersion mechanotherapy
WO2020223242A1 (en) * 2019-05-01 2020-11-05 Mechanobiologics Llc Systems and methods for cancer treatment

Also Published As

Publication number Publication date
JP2013135851A (ja) 2013-07-11
RU2007117501A (ru) 2008-11-20
EP2431075B1 (en) 2017-04-05
JP5268361B2 (ja) 2013-08-21
KR20070090880A (ko) 2007-09-06
RU2388504C2 (ru) 2010-05-10
EP1812110A1 (en) 2007-08-01
EP1812110B1 (en) 2013-06-19
KR101173716B1 (ko) 2012-08-13
ES2427426T3 (es) 2013-10-30
EP2431075A1 (en) 2012-03-21
GB0422525D0 (en) 2004-11-10
WO2006040597A1 (en) 2006-04-20
JP2008515581A (ja) 2008-05-15
JP5886767B2 (ja) 2016-03-16
CN102416226A (zh) 2012-04-18
US20110269693A1 (en) 2011-11-03
CA2582787A1 (en) 2006-04-20
JP2013006848A (ja) 2013-01-10
CN101102815B (zh) 2011-08-10
CN101102815A (zh) 2008-01-09
DK2431075T3 (en) 2017-07-17
DK1812110T3 (da) 2013-09-16
CA2582787C (en) 2014-06-10
US10406383B2 (en) 2019-09-10

Similar Documents

Publication Publication Date Title
US10406383B2 (en) Apparatus for treatment of dermatological conditions
Kozarev et al. Novel laser therapy in treatment of onychomycosis
KR101605527B1 (ko) 초음파 치료 시스템
US6882884B1 (en) Process for the stimulation of production of extracellular dermal proteins in human tissue
US20070078290A1 (en) Ultrasound-based treatment methods for therapeutic treatment of skin and subcutaneous tissues
US20070231255A1 (en) Method for the Treatment of Mammalian Skin Tissues Via Pulse Irradiation in the Presence of a Photoactive Compound
Rokhsar et al. Review of photorejuvenation: devices, cosmeceuticals, or both?
MXPA06014923A (es) Usos cosmeticos de radiacion electromagnetica.
US20120259252A1 (en) Coupling Emulsions for Use With Ultrasound Devices
Bailey et al. Management of keratinocyte carcinoma-Special considerations in the elderly
Alexiades Nonablative skin resurfacing for skin rejuvenation
Issa et al. Photodynamic Therapy
Wanner et al. Lasers for Adipose Tissue and Cellulite

Legal Events

Date Code Title Description
AS Assignment

Owner name: DERMAGLAIA LTD., UNITED KINGDOM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:LUEBCKE, PETER;REEL/FRAME:019119/0890

Effective date: 20070329

AS Assignment

Owner name: SONOVIA LIMITED, UNITED KINGDOM

Free format text: CHANGE OF NAME;ASSIGNOR:DERMAGLAIA LTD.;REEL/FRAME:022219/0711

Effective date: 20080221

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: SONOVIA HOLDINGS, LLC, KANSAS

Free format text: DEED OF ASSIGNMENT OF PATENT RIGHTS;ASSIGNOR:SONOVIA LTD.;REEL/FRAME:027307/0586

Effective date: 20111129

AS Assignment

Owner name: SONOVIA HOLDINGS LLC, KANSAS

Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF THE ASSIGNEE FROM SONOVIA HOLDINGS, LLC TO SONOVIA HOLDINGS LLC PREVIOUSLY RECORDED ON REEL 027307 FRAME 0586. ASSIGNOR(S) HEREBY CONFIRMS THE DEED OF ASSIGNMENT OF PATENT RIGHTS;ASSIGNOR:SONOVIA LTD.;REEL/FRAME:027316/0904

Effective date: 20111129