Methods and Systems for Ultrasound Assisted Delivery of a Medicant to Tissue

Abstract

This disclosure provides methods and systems for ultrasound assisted delivery of a medicant to tissue. The delivery of the medicant is enhanced by the application of high intensity ultrasound pulses, which generate an intertial cavitation effect, an acoustic streaming effect, or both. This disclosure also provides methods and systems for alleviating pain or swelling associated with the application of ultrasound energy by delivering an anesthetic across a stratum corneum layer according to the methods described herein.

1 . A method for ultrasound-assisted delivery of a medicant through a stratum corneum layer of a skin surface, the method comprising:
 a) administering the medicant to the skin surface;   b) coupling an ultrasound transducer to the medicant and the skin surface; and   c) applying a first pulsed acoustic energy field from the ultrasound transducer to the skin surface, the first pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 100 W/cm 2  to 100 kW/cm 2 , and a pulse width from 33 nanoseconds to 5 seconds, the first pulsed acoustic energy field generating inertial cavitation, acoustic streaming, or a combination thereof in the stratum corneum layer and driving the medicant through the stratum corneum layer.   
     
     
         2 . The method according to  claim 1 , wherein the first pulsed acoustic energy field is applied for sufficient time to drive an amount of medicant through the stratum corneum layer sufficient to achieve a clinical effect in a tissue beneath the stratum corneum layer. 
     
     
         3 . The method according to  claim 1 , wherein the first pulsed ultrasound energy has a pulse repetition rate from one pulse per 10 microseconds to one pulse per 100 seconds. 
     
     
         4 . The method according to  claim 1 , wherein the first pulsed acoustic energy field creates a thermal effect in a tissue beneath the stratum corneum layer, thereby raising a temperature of the tissue from 1° C. to 15° C. 
     
     
         5 . The method according to  claim 1 , the method further comprising:
 d) applying an alternating pulsed acoustic energy field between pulses of the first pulsed acoustic energy field, the alternating pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 5 W/cm 2  to 100,000 W/cm 2 , and a pulse width from 1 microsecond to 0.1 seconds, the first pulsed acoustic energy field and the alternating pulsed acoustic energy field generating inertial cavitation, acoustic streaming, or a combination thereof in the stratum corneum layer and driving the medicant through the stratum corneum layer.   
     
     
         6 . The method according to  claim 1 , the method further comprising:
 d) focusing a second pulsed acoustic energy field to a target volume at a depth beneath the stratum corneum layer, the second acoustic energy field configured to generate a thermal effect in the target volume, thereby ablating at least a portion of the target volume.   
     
     
         7 . The method according to  claim 6 , wherein the thermal effect raises a temperature in the target volume by from 15° C. to 65° C. without damaging an intervening tissue between the skin surface and the target volume. 
     
     
         8 . The method according to  claim 1 , the method further comprising:
 d) applying a second pulsed acoustic energy field focused to a depth beneath the skin surface, wherein the second pulsed acoustic energy field is emitted from the ultrasound transducer or a different ultrasound transducer, the second pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, an intensity from 5 W/cm 2  to 70,000 W/cm 2 , and a pulse width from 33 nanoseconds to 1 second, thereby creating acoustic streaming having a pressure from 10 kPa to 100 MPa and driving the medicant through an epidermis layer and into a dermis layer.   
     
     
         9 . The method according to  claim 8 , wherein the first pulsed acoustic energy field or the second pulsed acoustic energy field creates a thermal effect in the epidermis layer or the dermis layer, the thermal effect elevating a temperature by 1° C. to 15° C. 
     
     
         10 . The method according to  claim 9 , wherein the thermal effect increases blood perfusion within the epidermis layer or the dermis layer, thereby increasing absorption of the medicant into a bloodstream. 
     
     
         11 . The method according to  claim 1 , the method further comprising:
 d) applying a second pulsed acoustic energy field configured to provide an inertial cavitation effect at a depth of 0.5 millimeter to 7 millimeters beneath the skin surface, the second pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 3 W/cm 2  to 100 kW/cm 2 , and a pulse width from 33 nanoseconds to 100 seconds, thereby increasing dispersion of the medicant in an epidermis layer or a dermis layer beneath the skin surface.   
     
     
         12 . A method for reducing or eliminating pain generated by ultrasound treatment, the method comprising:
 a) applying a coupling medium comprising a medicant to a skin surface above a region of interest, the medicant comprising an anesthetic configured to numb a tissue in the region of interest;   b) coupling an ultrasound energy source to the coupling medium, the skin surface, and the region of interest;   c) directing a first acoustic energy field from the ultrasound energy source into the skin surface, thereby delivering the medicant into the tissue in the region of interest and numbing the tissue in a portion of the region of interest; and   d) directing a second acoustic energy field to a target volume in the tissue in the region of interest, the second acoustic energy field ablating the tissue in the target volume, the medicant reducing or eliminating pain generated by the ablating of the tissue.   
     
     
         13 . The method according to  claim 12 , wherein the first ultrasound energy has one or more of the following properties:
 a frequency from 1 MHz to 30 MHz;   a peak intensity from 100 W/cm 2  to 100,000 W/cm 2 ;   a pulse width from 33 nanoseconds to 5 seconds; and   a pulse repetition rate from one pulse per 10 microseconds to one pulse per 100 seconds.   
     
     
         14 . The method according to  claim 12 , wherein the first acoustic energy field creates a thermal effect in the tissue in the region of interest, thereby raising a temperature of the tissue from 1° C. to 15° C. 
     
     
         15 . The method according to  claim 12 , the method further comprising:
 e) applying a third acoustic energy field configured to provide an inertial cavitation effect in the target zone, the third acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 3 W/cm 2  to 100 kW/cm 2 , and a pulse width from 33 nanoseconds to 100 seconds, thereby dispersing the medicant in the target zone.   
     
     
         16 . The method according to  claim 12 , the method further comprising:
 e) coupling a second ultrasound energy source to the coupling medium, the skin surface, and the region of interest, the second acoustic energy field is generated by the second ultrasound energy source.   
     
     
         17 . The method according to  claim 12 , wherein the second acoustic energy field is generated by the ultrasound energy source. 
     
     
         18 . The method according to  claim 12 , wherein the anesthetic is selected from the group consisting of lidocaine, benzocaine, prilocaine, tetracaine, novocain, butamben, dibucaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine, tetracaine, and combinations thereof. 
     
     
         19 . A method of ultrasound-assisted transdermal drug delivery, the method comprising:
 a) contacting a skin surface with a coupling medium comprising a non-anesthetic medicant and an anesthetic;   b) coupling an ultrasound energy source to the coupling medium and the skin surface;   c) applying a first pulsed acoustic energy field from the ultrasound transducer to the skin surface, the first pulsed acoustic energy field having a peak intensity from 100 W/cm 2  to 100 kW/cm 2 , thereby driving the medicant and the anesthetic across a stratum corneum layer of the skin surface and into an epidermis layer beneath the skin surface, the anesthetic alleviating pain or swelling associated with the application of the first pulsed acoustic energy field.   
     
     
         20 . The method according to  claim 19 , wherein the first pulsed acoustic energy field has one or more of the following properties:
 a frequency from 1 MHz to 30 MHz;   a pulse width from 33 nanoseconds to 5 seconds; and   a pulse repetition rate from one pulse per 10 microseconds to one pulse per 100 seconds.   
     
     
         21 . The method according to  claim 19 , wherein the first pulsed acoustic energy field creates a thermal effect in a target zone of the epidermis layer, thereby raising a temperature of the target zone from 1° C. to 15° C. 
     
     
         22 . The method according to  claim 19 , the method further comprising:
 d) applying an alternating pulsed acoustic energy field between pulses of the first pulsed acoustic energy field, the alternating pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 5 W/cm 2  to 100,000 W/cm 2 , and a pulse width from 33 nanoseconds to 0.1 seconds, the first pulsed acoustic energy field and the alternating pulsed acoustic energy field generating inertial cavitation, acoustic streaming, or a combination thereof in the stratum corneum layer and driving the medicant through the stratum corneum layer.   
     
     
         23 . The method according to  claim 19 , the method further comprising:
 d) focusing a second pulsed acoustic energy field to a target volume within the epidermis layer, the second acoustic energy field configured to generate a thermal effect in the target volume, thereby ablating at least a portion of the target volume.   
     
     
         24 . The method according to  claim 23 , wherein the thermal effect raises a temperature in the target volume by from 15° C. to 65° C. without damaging an intervening tissue between the skin surface and the target volume. 
     
     
         25 . The method according to  claim 19 , the method further comprising:
 d) applying a second pulsed acoustic energy field focused to a depth within the epidermis layer, wherein the second pulsed acoustic energy field is emitted from the ultrasound transducer or a different ultrasound transducer, the second pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, an intensity from 5 W/cm 2  to 70,000 W/cm 2 , and a pulse width from 33 nanoseconds to 1 second, thereby creating acoustic streaming having a pressure from 10 kPa to 100 MPa and driving the medicant through the epidermis layer and into a dermis layer.   
     
     
         26 . The method according to  claim 25 , wherein the first pulsed acoustic energy field or the second pulsed acoustic energy field creates a thermal effect in the epidermis layer or the dermis layer, the thermal effect elevating a temperature by 1° C. to 15° C. 
     
     
         27 . The method according to  claim 26 , wherein the thermal effect increases blood perfusion within the epidermis layer or the dermis layer, thereby increasing absorption of the medicant into a bloodstream. 
     
     
         28 . The method according to  claim 25 , the method comprising:
 d) focusing a third pulsed acoustic energy field to a target volume within the dermis layer, the third acoustic energy field configured to generate a thermal effect in the target volume, thereby ablating at least a portion of the target volume.   
     
     
         29 . The method according to  claim 28 , wherein the thermal effect raises a temperature in the target volume by from 15° C. to 65° C. without damaging an intervening tissue between the skin surface and the target volume. 
     
     
         30 . The method according to  claim 19 , the method further comprising:
 d) applying a second pulsed acoustic energy field configured to provide an inertial cavitation effect at a depth of 0.5 millimeter to 7 millimeters beneath the skin surface, the second pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 3 W/cm 2  to 100 kW/cm 2 , and a pulse width from 33 nanoseconds to 100 seconds, thereby increasing dispersion of the medicant in an epidermis layer or a dermis layer beneath the skin surface.