WO2001032232A2 - Method of forming micropores in skin - Google Patents
Method of forming micropores in skin Download PDFInfo
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- WO2001032232A2 WO2001032232A2 PCT/US2000/041754 US0041754W WO0132232A2 WO 2001032232 A2 WO2001032232 A2 WO 2001032232A2 US 0041754 W US0041754 W US 0041754W WO 0132232 A2 WO0132232 A2 WO 0132232A2
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- WO
- WIPO (PCT)
- Prior art keywords
- sonic
- range
- ultrasonic radiation
- stratum
- ultrasound
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
Definitions
- the present invention relates to a method and an apparatus for forming micropores in the skin for transdermal drug delivery and more particularly to transdermal delivery of drugs and other molecules with high molecular weight using sonic and/or ultrasonic radiation.
- Transdermal delivery of drugs offers several advantages over conventional delivery methods including oral and injection methods. It delivers a predetermined drug dose to a localized area with a controlled steady rate and uniform distribution, is non-invasive, convenient and painless.
- Transdermal delivery of drugs requires transport of the drug molecules through the stratum corneum, i.e., the outermost layer of the skin.
- the stratum corneum (SC) provides a daunting chemical barrier to any chemical entering the body and only small molecules having a molecular weight of less than 500 Da (Daltons) can passively diffuse through the skin at rates resulting in therapeutic effects.
- a Dal ton is defined as a unit of molecular weight as compared to the hydrogen molecule.
- iontophoresis utilizes low electric fields to drive drug molecules into the skin, as described in U.S. 5,224,927.
- iontophoresis is limited to ionizable drugs and molecules and is ineffective for molecules having a molecular weight greater that about 7 kDa, as described by N. G. Turner, et al., in Pharm. Research- 14, 1322- 1331, 1997.
- the electroporation and electroinco ⁇ oration methods utilize high voltage electric pulses of 150 V that are directly applied to the skin, as described in U.S. 5,019,034.
- the electric pulses help open pores in the skin thus allowing molecules above 7 kDa to enter the skin.
- the use of high electric voltages poses safety problems and requires complicated equipment.
- the drugs need to be driven through the pores by some secondary means, as described in U.S. Pat. Nr. 5,688,233, which further complicates the application.
- the sonophoresis method utilizes ultrasound and has been shown to be capable of delivering molecules up to 48 kDa, as described in U.S. Pat. Nr. 5,814,599 and U.S 5,947,921. However, the rate of delivery is extremely low thus rendering it impractical.
- Chemical enhancers such as unsaturated fatty acids, saturated fatty acids, their esters and terpenes can increase the flux though the SC for drugs having large molecular weight, such as Estradiol, Testosterone and also polar drugs such as hydrochloride salts of basic drugs (e.g. Propranolol.HCl), as described by J. R. Kunta, et al., in J.Pharm. Sci. 86, 1369-1373, 1997 and in U.S. Pat. Nr. 5,947,921.
- basic drugs e.g. Propranolol.HCl
- chemical enhancers have serious formulation problems, can cause skin irritations and unwanted plasticization of a transdermal patch adhesive used for their application and their effectiveness depends upon the drug type and their application method. It would be advantageous to provide a method for transdermal delivery of any size drug molecules at high delivery rates.
- the invention provides a method of forming pores in the stratum corneum including applying an aqueous material to a surface area of the stratum corneum and applying sonic and/or ultrasonic radiation to the aqueous material.
- the sonic and/or ultrasonic radiation has a frequency in the range of 10 KHz and 5 MHz and is applied at an intensity, for a period of time and at a distance from the surface area of the stratum corneum effective to generate cavitation bubbles on the surface area of the stratum corneum.
- the cavitation bubbles collapse and transfer their energy into the stratum corneum causing the formation of pores.
- Implementations of the invention may include one or more of the following features.
- the sonic and/or ultrasonic radiation may have a frequency of 20 KHz and intensity in the range of 5 W/cm and 55 W/ cm " .
- the ultrasound may be applied at a distance from the surface area of the stratum corneum in the range of 1 millimeter to 10 millimeters. In one example, the distance may be 4 millimeters.
- the sonic and/or ultrasonic radiation may be continuous or pulsed and it may be applied for a period of time in the range of about 30 seconds to 1 minute for continuous exposure and in the range of 10 minutes to 20 minutes for pulsed exposure with a 5% duty cycle.
- the pores may have a diameter in the range of 1 micrometer to 100 micrometers
- the invention features a method of transporting molecules across the stratum corneum including applying an aqueous material containing the molecules to a surface area of the stratum corneum.
- the sonic and/or ultrasonic radiation has a frequency in the range of 10 KHz and 5 MHz and is applied at an intensity, for a period of time and at a distance from the surface area of the stratum corneum effective to generate cavitation bubbles on the surface area of the stratum corneum.
- the cavitation bubbles collapse and transfer their energy into the stratum corneum causing the formation of pores.
- the sonic and/or ultrasonic radiation is applied at an intensity and at a distance from the stratum corneum effective to generate ultrasonic jets, which ultrasonic jets then drive the molecules through the formed pores across the stratum corneum.
- the molecules may have a molecular weight in the range of 18 Da to 100 kDa.
- the molecules may be drugs selected from the group consisting of analgesics, anesthetics antibiotics, anticoagulants, antidotes, antihistamines, miscellaneous anti-infective, anti- inflammatory steroidal and non-steroidal, antineoplastics, antivirals, appetite suppressant, biologicals, cardiovascular agents, contraceptives, central nervous system stimulants, dermatologicals.
- diabetes agents enzymes, digestants, anti-fungal, hair growth stimulants, he ⁇ es treatment agents, hormones, immunosuppressives, anti-insect sting agents, anti-migraine drugs, muscle relaxants, narcotic antagonists, plasma fractions, psychotropics, anti-Parkinson, Alzheimer, Aids, anti-wards, anti-cancer, anti- osteoporosis, and genetic materials.
- the molecules may be active ingredients selected from the group consisting of vitamins, cosmoceuticals and nutroceuticals.
- the invention features an apparatus for forming pores in the stratum corneum including a container containing an aqueous material, the container being attached to a surface area of the stratum corneum so that the aqueous material is in contact with the surface area of the stratum corneum. and an ultrasound horn submerged in the container applying sonic and/or ultrasonic radiation to the aqueous material.
- the sonic and/or ultrasonic radiation has a frequency in the range of 10 KHz and 5 MHz and is applied at an intensity, for a period of time and at a distance from the surface area of the stratum corneum effective to generate cavitation bubbles on the surface area of the stratum corneum.
- the cavitation bubbles collapse and transfer their energy into the stratum corneum causing the formation of pores.
- the invention features an apparatus for transporting molecules across the stratum corneum including a container containing an aqueous material and the molecules, the container being attached to a surface area of the stratum comeum so that the aqueous material and the molecules are in contact with the surface area of the stratum comeum and an ultrasound hom submerged in the container applying sonic and/or ultrasonic radiation to the aqueous material.
- the sonic and/or ultrasonic radiation has a frequency in the range of 10 KHz and 5 MHz and is applied at an intensity, for a period of time and at a distance from the surface area of the stratum comeum effective to generate cavitation bubbles on the surface area of the stratum corneum.
- the cavitation bubbles collapse and transfer their energy into the stratum corneum causing the formation of pores.
- the sonic and/or ultrasonic radiation is applied at an intensity and at a distance from the stratum corneum effective to generate ultrasonic jets, which ultrasonic jets then drive the molecules through the formed pores across the stratum comeum.
- the invention provides a method of forming fractional openings in the stratum comeum, and delivery of high molecular weight drugs through the skin into the bloodstream. Drugs with molecular weights higher than 500 Da are transferred at high flow rates sufficient to enable therapeutic delivery of an appropriate volumetric dose in a short time without the danger associated with high voltages or chemical side effects such as skin irritations, or plasticization of a transdermal patch adhesive.
- This method is not limited to ionic type drugs and does not require complicated equipment.
- FIG. 1 is a schematic representation of an apparatus for in vitro sonoporation of skin.
- FIG 2 is a schematic representation of an ultrasound horn
- FIG 3 is a graph depicting a pulsed ultrasound wave
- FIG 4 is a cross-sectional side ⁇ ⁇ ew of the sample holder assembh of FIG 1
- FIG 5 is a schematic representation of a cross-section of a human skin sample
- FIG 6 is a detailed view of the stratum corneum area A of FIG 5
- FIG 7 is a schematic representation of a cross-section oi a human skin sample during exposure to sonic and/or ultrasonic radiation
- FIG 8 is a schematic representation of a cross-section of a human skin sample after exposure to sonic and/or ultrasonic radiation
- FIG 9 is an optical image of a stratum corneum sample under 40X magnification before exposure to ultrasound
- FIG 10 is an optical image of a stratum corneum sample under 40X magnification after exposure to ultrasound according to this invention
- FIG 1 1 is a graph depicting flux of 2 5kDa octa-1-lys ⁇ ne-FITC through a stratum comeum (SC) sample as a function of the distance of the ultrasound horn from the top surface of the SC sample
- FIG 1 1A is a schematic representation of the ultrasonic lets at an ultrasound intensit ⁇ of 18 W/cm 2
- FIG 1 IB is a schematic representation of the ultrasonic jets at an ultrasound lntensit 1 of 37 W/cm 2
- FIG. 11A is a schematic representation of the ultrasonic jets at an ultrasound intensity
- FIG. 12 is a graph depicting flux of 2.5kDa octa-1-lysine-FITC through a stratum comeum (SC) sample as a function of the ultrasound intensity.
- SC stratum comeum
- FIG. 13 is a graph depicting cumulative flux of 2.5 kDa octa-1-lysine-FITC through a stratum comeum (SC) sample as a function of the ultrasound exposure time.
- SC stratum comeum
- FIG. 14 is a confocal microscopy image of a cross-section of the human epidermis exposed to 2.5kDa octa-1-lysine-FITC.
- FIG. 15 is a confocal microscopy image of a cross-section of the human epidermis exposed to 2.5kDa octa-1-lysine-FITC and sonic and/or ultrasonic radiation.
- an apparatus 100 for performing in vitro sonoporation and transdermal drug delivery includes an ultrasound equipment assembly 110 and a Franz cell assembly 120.
- the ultrasound equipment assembly 1 10 includes a power supply 1 17 connected to an ultrasound transducer 1 13 by an electric cable 1 15.
- the power supply 1 17 provides energy to the transducer 1 13 and the transducer converts the electrical energy into ultrasound waves 1 12.
- the ultrasound waves 1 12 are transferred into an aqueous medium 123 by a horn 11 1, which is attached to the transducer 1 13.
- the horn 1 1 1 has a tip 1 14, which is submerged in the aqueous medium 123.
- the ultrasound equipment assembly 110 is a commercially available Sonifier model 450, manufactured by Branson Instruments Inc., Danbury, Connecticut.
- the hom 111 is a tapered cylinder having a length 118 of 15 cm and a tip cross-sectional area 116 of 1cm " , shown in FIG. 2.
- the transducer 1 13 is an unfocused single band transducer generating ultrasound waves 1 12 having a frequency in the range of 10 KHz to 5 MHz and intensity in the range of 5 W/ cm " and 55 W/ cm .
- the ultrasound waves are pulses 1 19 having a frequency of 20 KHz and intensity 1 19c of 20 W/ cm " .
- the pulse width 1 19a is 0.5 seconds
- the time interval 119b between the end of one pulse and the beginning of the next is 9.5 seconds
- the period of the ultrasound wave is 10 seconds.
- the skin is exposed to ultrasound for 20 minutes with a 5% duty cycle (i.e., 120 pulses with each pulse providing ultrasound energy for 0.5 seconds) resulting in a total of 1 minute of continuous ultrasound exposure.
- the Franz cell assembly 120 is custom made and includes a donor compartment 122, a receiver compartment 124 and a sample holder assembly 140 mounted between the donor and the receiver compartments.
- both the donor compartment 122 and the receiver compartment are made from commercially available O-ring joint glass tubes, purchased from Krackeler Scientific, Inc., Albany, NY 12201.
- the donor compartment glass tube 130 has a length 131 of 6 cm. a first end 133 and a second end 134, both ends having openings with a diameter 132 of 1.6 cm.
- the second end 134 has a flange 135 with a groove 136 accommodating an O-ring 137.
- the receiver compartment 124 has a cylindrical main body 142 with a length 148 of 3 cm.
- the main body 142 has a first end 143, a second end 144. and a side port 145 connected to a second cylindrical tube 146.
- the first end 143 of the receiver compartment 124 has a flange 147 and an opening with the same diameter 149 as the opening of the second end 134 of the donor compartment 122.
- the second end 144 is closed.
- the donor compartment is placed on top of the receiver compartment so that the open ends 134 and 143 are aligned.
- a sample of human cadaver epidermis 150 supported on a membrane 152 is mounted between the flange 135 of the second end 134 of the donor compartment 122 and the flange 147 of the first end 143 of the receiver compartment 124.
- a clamp 155 holds the two compartments 122 and 124. together.
- the clamp 155 applies pressure on the flanges 135 and 147 through a spring 156.
- the applied pressure squeezes the O-ring 137 into the groove 136 resulting in a tight liquid proof seal.
- the support membrane is a spun-bonded non-woven open mesh material manufactured by Du Pont. Wilmington, DE 19898. The membrane is used to simulate the in vivo support of the epidermis by the dermis and to reduce potential damage of the skin sample.
- a cross-section of human skin 200 includes a top layer 210, a middle layer 220 and a bottom layer 230.
- the top layer 210 is called the stratum comeum, has a thickness of about 15 micrometers and is made of multiple layers of keratinized proteins 21 1. surrounded by lipid bilayers 212. shown in FIG. 6.
- Keratinized proteins 21 1 or keratinocytes are dead cells filled with keratin fibers. Each keratinocyte has a plate-like structure having an area with a diameter of approximately 15 to 20 micrometers and a thickness of 1 micrometer.
- the keratinocytes are surrounded by lipids and are arranged next to each other forming layers, which are separated from each other by lipid bilayers 212.
- the lipid bilayers 212 have a thickness of approximately 50 nanometers.
- This structure of the stratum comeum resembles a "brick wall " ' with the keratinocytes forming the "bricks” and the lipids forming the "cement” that holds the "bricks” together.
- This highly ordered structure makes the stratum comeum impermeable to many drugs.
- the middle layer 220 lies below the stratum corneum and is called the viable epidermis.
- the viable epidermis 220 is made of living cells and has a hydrophilic character.
- the bottom layer 230 lying below the viable epidermis is the dermis. At the interface of the viable epidermis 220 and the dermis 230 reside the endings of a capillary vascular system 240.
- a sample of stratum corneum is extracted from postmortem human skin.
- the postmortem human skin is obtained from the thigh of an anonymous adult of seventy- one years old, supplied by the Michigan Tissue Bank, Lansing, MI 48909.
- the skin sample is stored at -50 °C in a freezer and is used within a few weeks post mortem.
- the stratum co eum and part of the epidermis are separated from the dermis by the heat stripping method.
- the skin is thawed and placed in a bath of a saline solution, which has a concentration of 9 g/liter of sodium chloride and a temperature of 55 °C.
- the skin sample is kept in the solution for two minutes and then is removed and placed in a similar saline solution having a temperature of 23 °C.
- the outer layers of the stratum corneum and part of the viable epidermis are then manually separated from the skin sample by using ones fingers.
- the stratum corneum samples have a thickness in the range between 40 and 50 micrometers.
- the sample of stratum corneum 150 is placed in the sample holder assembly 140.
- the sample assembly 140 is placed between the donor 122 and receiver compartment 124 of the Franz cell 120.
- HEPES stands for N-[2- Hydroxyethyl]piperazine-N ' -[2-ethanesulfonic acid] and is obtained from Sigma Chemicals. St. Louis. MO 63178-9916.
- 2.5 kDa octa-1-lysine-FITC denotes octa-1-lysine tagged with fluorescein isothiocyanate and is obtained from Peptide Technologies Co ⁇ .. Gaithersburg. MD 20877.
- the tip of the ultrasound horn 1 14 is submerged in the solution 123 of the donor compartment and is kept at a preset distance 180 above the top surface 151 of the stratum corneum sample. The distance 180 between the tip 1 14 and the top surface 151 of the stratum comeum is varied between 1 and 10 millimeters.
- the power supply 117 is turned on and the transducer 113 generates ultrasound pressure waves 112 having alternating positive and negative pressure cycles at a frequency of 20 KHz.
- the submerged ultrasound tip 114 transfers the ultrasound waves in the solution 123 of the donor compartment.
- the ultrasound waves propagate in the aqueous solution 123 and impinge upon the top surface 151 of the stratum corneum sample.
- the intensity of the ultrasound waves is varied between 5 and 55 W/cm " and is measured calorimetrically with a thermocouple 160.
- the thermocouple 160 has a junction 162 of two 100 ⁇ m diameter wires of copper and constantan and is affixed in the human cadaver skin 150.
- the thermocouple signal is measured using a Keithley Model 196 digital multimeter.
- c p is the heat capacity of water, which is equal to 1 cal/g°C
- m is a mass of aqueous solution exposed to ultrasound, which in one example is 4 g.
- ⁇ T is the temperature rise during an ultrasound exposure time of 5 sec.
- t is the ultrasound exposure time.
- A is the area of the ultrasound emission, which in one example is 1 cm “
- 4.19 is a unit conversion factor of "calories " into “joules”.
- the stratum corneum sample is exposed to the ultrasound for a predetermined time.
- the exposure time is 20 min with a 5% duty cycle of pulsed ultrasound or a total of 1 minute of continuous ultrasound.
- a schematic diagram of a cross-section of the human skin exposed to 20 KHz ultrasound shows formation of cavitations 500 in the top surface 215 of the stratum corneum 210.
- Cavitations are small gaseous cavities that are formed in an aqueous solution during the negative pressure cycles of the ultrasound pressure waves. These small gaseous cavities continue to grow and build up high energy throughout subsequent pressure cycles until they reach a critical size and energy and then collapse. When they collapse close to the top surface 151 of the stratum comeum they transfer their high energy to the stratum comeum causing rupture of the lipid bilayers 212 or the formation of pores in the stratum comeum. Cavitations may also occur inside the stratum comeum where air pockets exist.
- a schematic cross-section of the stratum comeum 210 that has been exposed to 20 KHz ultrasound depicts pores 600 generated by the ultrasound. The pores are made visible under magnifying confocal light microscopy.
- FIG. 9 an optical image of the top surface 151 of a stratum comeum sample before exposure to ultrasound depicts a well ordered cellular structure of the keratinized cells 21 1.
- the same sample is shown in FIG. 10 after exposure to ultrasound of a frequency of 20 KHz and intensity of 20 W/cm".
- Pores 600 black regions are visible under a magnification of 40X. The observation is performed 1 - 2 hrs after the ultrasound exposure.
- the pores 600 have a diameter in the range of 1 to 100 micrometers.
- the formation of pores during exposure of the stratum corneum to sonic and/or ultrasonic radiation of a certain frequency, intensity and at a predetermined distance is utilized for transdermal delivery of drugs.
- the donor compartment 122 of the Franz cell 120 is filled with 4 milliliters of 0.1064 mM of octa-1- lysine-4-FITC.
- Octa-l-lysine-4-FITC has a molecule size of 2.5 kDa and has four fluorescein isothiocyanate molecules attached.
- the receiver compartment 124 is filled with 8 milliliters of 25 mM of HEPES buffer having a pH of 7.4.
- a magnetic stirrer 126 continuously stirs the HEPES solution at a speed of 500 ⁇ m. Both solutions 123 and 125 are prepared with deionized water that has a resistivity of more than 18 Mohms/cm.
- a stratum comeum sample 150 having a total area of 8 cm 2 is mounted in the sample holder 140. In one example, the surface area of the stratum comeum sample exposed to ultrasound is 2.5 cm 2 . The structural integrity of the sample is assured by measuring the skin resistance. The skin resistance is measured by applying a voltage of 1.5 V and 1 Hz across the skin. Only samples with resistance of more than 50 Kohms are used. The ultrasound hom 1 11 is submerged in the donor solution 123 at a preset distance from the top surface of the stratum comeum sample.
- the ultrasound hom 1 1 1 is preset at a distance 180 of 13 millimeters from the top surface of the stratum corneum sample.
- the distance 180 of the ultrasound tip 1 14 from the top surface of the stratum comeum 151 is measured with a caliper.
- the temperature of the 2.5 kDa octa -l-lysine-4- FITC solution is maintained between 25 °C and 30 °C.
- the flux of 2.5 kDa octa-l-lysine-4-FITC through the human stratum comeum sample is depicted as a function of the distance 180 of the ultrasound tip 1 14 from the top surface 151 of the stratum corneum sample 150.
- the sample is exposed to sonic and/or ultrasonic radiation with a frequency of 20 KHz and a pulsed intensity of 20 W/cm 2 with a 5% duty cycle.
- the amount of octa-l-lysine-4-FITC transferred across the stratum comeum sample is determined by fluorometric measurements of the receiver solution 125. The fluorometric measurements are performed with a Hitachi F-2000 Fluorescence spectrometer.
- the excitation wavelength is 497 nm and the emission of the fluorescein tagged 2.5kDa octa-l-lysine-4-FITC is at 522 nanometers.
- a sample of 0.8 milliliters of the receiver solution 125 is collected with a micropipette through the side port tube 146 and the same amount of HEPES solution is added back into the receiver solution. The fluorescence measurements of the subsequent solution samples are corrected for the dilution factor.
- the flux of 2.5kDa octa-l-lysine-4-FITC across the stratum corneum sample initially increases with increasing distance of the ultrasound tip 1 14 from the top surface 151 of the sample (Region I). It reaches a maximum at a distance of between 2 and 4 millimeters (Region II) and then decreases with increasing distance (Region III). At about 4 millimeters distance of the ultrasound tip 1 14 from the surface of the stratum comeum 151 the molecular transfer of octa-l-lysine-4-FITC is optimal.
- FIGs. 1 1A. 1 IB and 1 1C depict the ultrasonic jets 170 at ultrasound intensities of approximately 18 W/cm " , 37 W/cm " and 55 W/cnr. respectively.
- the ultrasonic jets 170 are visualized by sending light 165 into the donor compartment 122.
- the flux of 2.5 kDa octa-1-lysine-FITC through a sample of stratum comeum is depicted as a function of ultrasound intensity.
- the ultrasound intensity is varied between 5 and 55 W/cm 2 for a 20 KHz pulsed excitation at 5 % of duty cycle.
- the ultrasound tip 1 14 is kept at a distance of 2 millimeters from the top surface of the stratum corneum sample 151.
- Optimum molecular transfer occurs at an ultrasound intensity of about 18 W/cm .
- the cumulative flux of 2.5 kDa octa-1-lysine-FITC through a sample of stratum corneum is depicted as a function of the exposure time to ultrasound excitation of 20 KHz frequency, 5% duty cycle, 37 W/cm 2 and at distance of 4 mm from the sample surface.
- the ultrasound power is on and as the exposure time increases pores are formed and the number of molecules of 2.5 kDa octa-1-lysine-FITC transferring across the stratum corneum increases.
- Region II the ultrasound power is turned off and we observe practically no transfer of the molecules across the stratum comeum.
- the permeability of the stratum corneum for molecules of 2.5 kDa octa-1-lysine-FITC and 2.5 kDa octa-1-lysine-FITC exposed to sonic and/or ultrasonic radiation is summarized for the ultrasound conditions of this invention that cause sonoporation and ultrasonic jet formation.
- Table 1 Comparison of stratum comeum permeability caused by sonophoresis (prior art) and sonoporation (this invention).
- confocal microscopy images of the cross-section of the human epidermis samples exposed to 0.1 mM of 2.5 kDa octa-1-lysine-FITC solution with and without the sonic and/or ultrasonic radiation, respectively, are obtained under laser light excitation of 488 nanometers of the FITC fluorochrome.
- the images are obtained using a LaserSha ⁇ MRC 1024 Confocal Laser Scanning Microscope manufactured by BioRad Laboratories, Hercules, CA.
- both the stratum comeum layer 210 and the viable epidermis 220 emit the characteristic FITC fluorescence
- the top surface of the stratum corneum 210 emits the characteristic FITC fluorescence.
- transdermal transfer of 2.5 octa- 1-lysine-FITC occurs only under ultrasound exposure.
- the micro-pores 600 generated by the ultrasound are not permanent disturbances of the epidermis but rather transient and resilient openings that close when the ultrasound exposure is removed leaving behind only subtle marking of their presence on the surface of the stratum corneum.
- Molecules selected from the group of active ingredients consisting of vitamins, cosmoceuticals and nutroceuticals may also be transferred through the stratum corneum using the sonoporation method of this invention.
- the sonic and/or ultrasonic radiation may be continuous or pulsed having a frequency in the range of 1 KHz and 5 MHz. Pulsed sonic and/or ultrasonic radiation has the advantage of not raising the temperature of the sample, whereas continuous ultrasound has the advantage of offering short treatment times.
- the sonic and/or ultrasonic radiation may be applied for a period of time in the range of about 30 seconds to 1 minute for continuous exposure and in the range of 10 minutes to 20 minutes for pulsed exposure with a 5% duty cycle.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU37912/01A AU3791201A (en) | 1999-11-02 | 2000-11-01 | Method of forming micropores in skin |
JP2001534436A JP2004520852A (en) | 1999-11-02 | 2000-11-01 | How to form micropores in the skin |
CA002389626A CA2389626A1 (en) | 1999-11-02 | 2000-11-01 | Method of forming micropores in skin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US16314699P | 1999-11-02 | 1999-11-02 | |
US60/163,146 | 1999-11-02 |
Publications (2)
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WO2001032232A2 true WO2001032232A2 (en) | 2001-05-10 |
WO2001032232A3 WO2001032232A3 (en) | 2002-08-01 |
Family
ID=22588686
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2000/041754 WO2001032232A2 (en) | 1999-11-02 | 2000-11-01 | Method of forming micropores in skin |
Country Status (4)
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JP (1) | JP2004520852A (en) |
AU (1) | AU3791201A (en) |
CA (1) | CA2389626A1 (en) |
WO (1) | WO2001032232A2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007028984A1 (en) * | 2005-09-08 | 2007-03-15 | University Of Dundee | Apparatus and method for sonoporation |
US7923897B2 (en) | 2005-07-04 | 2011-04-12 | Sonopore, Ltd. | Sonic fine-hole forming apparatus |
CN111511440A (en) * | 2017-12-22 | 2020-08-07 | 自由波有限公司 | System and method for inducing sonoporation of drugs into cancer cells |
US11241277B2 (en) | 2017-08-25 | 2022-02-08 | Lutronic Corporation | Skin treatment apparatus using RF energy and method for skin treatment using same |
Citations (2)
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 |
US5421816A (en) * | 1992-10-14 | 1995-06-06 | Endodermic Medical Technologies Company | Ultrasonic transdermal drug delivery system |
-
2000
- 2000-11-01 JP JP2001534436A patent/JP2004520852A/en active Pending
- 2000-11-01 CA CA002389626A patent/CA2389626A1/en not_active Abandoned
- 2000-11-01 AU AU37912/01A patent/AU3791201A/en not_active Abandoned
- 2000-11-01 WO PCT/US2000/041754 patent/WO2001032232A2/en active Application Filing
Patent Citations (2)
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 |
US5421816A (en) * | 1992-10-14 | 1995-06-06 | Endodermic Medical Technologies Company | Ultrasonic transdermal drug delivery system |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7923897B2 (en) | 2005-07-04 | 2011-04-12 | Sonopore, Ltd. | Sonic fine-hole forming apparatus |
WO2007028984A1 (en) * | 2005-09-08 | 2007-03-15 | University Of Dundee | Apparatus and method for sonoporation |
US11241277B2 (en) | 2017-08-25 | 2022-02-08 | Lutronic Corporation | Skin treatment apparatus using RF energy and method for skin treatment using same |
CN111511440A (en) * | 2017-12-22 | 2020-08-07 | 自由波有限公司 | System and method for inducing sonoporation of drugs into cancer cells |
Also Published As
Publication number | Publication date |
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AU3791201A (en) | 2001-05-14 |
CA2389626A1 (en) | 2001-05-10 |
WO2001032232A3 (en) | 2002-08-01 |
JP2004520852A (en) | 2004-07-15 |
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