Abstract:
An apparatus for performing in-vivo sonoporation of a skin area and transdermal and/or intradermal delivery of a drug solution includes a container having an end adjacent the skin area and containing the drug solution. The container further includes an ultrasound horn having a tip submerged in the drug solution for applying ultrasound radiation to the drug solution. The ultrasound radiation has a frequency in the range of 15 KHz and 1 MHz and is applied at an intensity, for a period of time and at a distance from said skin area effective to generate cavitation bubbles. The cavitation bubbles collapse and transfer their energy into the skin area, thus causing the formation of pores in the skin area. The ultrasound radiation intensity and distance from the skin area are also effective in generating ultrasonic jets, which ultrasonic jets then drive the drug solution through the end adjacent the skin area and the formed pores into the skin.

Description:
FIELD OF THE INVENTION  
         [0001]    The present invention relates to a method and an apparatus for transdermal and/or intradermal delivery of drugs by sonoporation and more particularly to in-vivo transdermal and/or intradermal delivery of drugs.  
         BACKGROUND OF THE INVENTION  
         [0002]    Transdermal and/or intradermal delivery of drugs offer 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.  
           [0003]    Transdermal and/or intradermal delivery of drugs require transport of the drug molecules through the stratum corneum, i.e., the outermost layer of the skin. The stratum corneum (SC) provides a formidable 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 Dalton is defined as a unit of mass equal to {fraction (1/12)} the mass of a carbon-12 atom, according to “Steadman&#39;s Electronic Medical Dictionary” published by Williams and Wilkins (1996).  
           [0004]    In co-pending patent application entitled “Method of forming micropores in skin”, incorporated herein by reference, sonoporation has been proposed as a method to facilitate transdermal and/or intradermal delivery of molecules larger than 500 Da and to increase the rate of drug delivery through the SC. The sonoporation apparatus described in the referenced application is not practical for in-vivo drug delivery and in particular for treating humans.  
           [0005]    It would be advantageous to provide a method and an apparatus for in-vivo transdermal and/or intradermal delivery of any size drug molecules.  
         SUMMARY OF THE INVENTION  
         [0006]    In general, in one aspect, the invention provides an apparatus for performing in-vivo sonoporation of a skin area and transdermal and/or intradermal delivery of a drug solution including a container having an end covered with a porous membrane and containing the drug solution and an ultrasound horn having a tip submerged in the drug solution. The ultrasound horn applies ultrasound radiation to the drug solution. The ultrasound radiation has a frequency in the range of 15 KHz and 1 MHz and is applied at an intensity, for a period of time and at a distance from said skin area effective to generate cavitation bubbles. The cavitation bubbles collapse and transfer their energy into the skin area thus causing the formation of pores in the skin area. The ultrasound radiation intensity and distance from the skin area are also effective in generating ultrasonic jets, which ultrasonic jets then drive the drug solution through the porous membrane and the formed pores into the skin area.  
           [0007]    Implementations of the invention may include one or more of the following features. The membrane may have pores with a diameter of 100 micrometers. The membrane may be hydrophobic. The tip may be removable connected to the ultrasound horn and it may have a distal end surface, which is flat or concave. The distal end surface may have a plurality of depressions. The tip may also have a body having markings indicating the amount of the drug solution contained in the container. A removable protective film may cover the membrane. The container may have an outer wall, an inner wall and an absorbent wick placed between the inner and outer wall. The wick absorbs any excess drug solution that is not driven into the skin area through the formed pores and it may be made of highly absorbent and hydrophilic material such as absorbent cellulose material, polyvinyl alcohol sponge, Sodium Carboxy-Methyl Cellulose (CMC), blotting paper and any other spongy materials.  
           [0008]    The container inner wall may have first and second grooves and tip may have a body having first and second grooves. The tip is inserted into the container and placed so that the first and second grooves of the tip body are opposite the first and second grooves of the container inner wall. This arrangement defines first and second spaces for accommodating first and second o-rings, respectively. The container may also have an inlet septum for filling it with the solution. The container may be a cylinder made of a transparent material and/or plastic material.  
           [0009]    The ultrasound frequency may be 20 KHz and the ultrasound intensity may be in the range of 5 W/cm 2  and 55 W/cm 2 . The tip may have a distal end located at a distance from the membrane in the range of 1 millimeter to 10 millimeters. The ultrasound radiation may be continuous or pulsed and it may be applied for a period of time in the range of about 30 seconds to 5 minutes, preferably 1 minute for continuous exposure or about 10 minutes to 20 minutes for pulsed exposure with a 5% duty cycle, respectively. The formed pores may have a diameter in the range of 1 micrometer to 100 micrometers.  
           [0010]    In general, in another aspect, the invention features a method of performing in-vivo sonoporation of a skin area and transdermal and/or intradermal delivery of a drug solution. The method includes providing a container containing a predetermined amount of the drug solution and having a first end and a second end, the second end being covered with a porous membrane. Next a tip of an ultrasound horn is submerged in the drug solution through the first end of the container and then the porous membrane is placed in contact with the skin area. The ultrasound radiation is then turned on having a frequency in the range of 15 KHz and 1 MHz. The ultrasound radiation is applied with an intensity, for a period of time and at a distance from the skin area effective to generate cavitation bubbles. The cavitation bubbles collapse and transfer their energy into the skin area thus causing the formation of pores in the skin area. The ultrasound radiation intensity and distance from the skin area are also effective in generating ultrasonic jets, which ultrasonic jets then drive the drug solution through the porous membrane and the formed pores into the skin area.  
           [0011]    Among the advantages of this invention may be one or more of the following. The apparatus allows a painless and rapid delivery of drugs through the skin for either topical or systemic therapy. The apparatus allows coupling of the ultrasound radiation to a container containing the drug solution without dampening the ultrasound intensity.  
           [0012]    The details of one or more embodiments of the invention are set forth in the accompanying drawings and description below. Other features, objects and advantages of the invention will be apparent from the following description of the preferred embodiments, the drawings and from the claims. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0013]    [0013]FIG. 1 is a schematic representation of in-vivo transdermal and/or intradermal delivery of an anti-inflammatory drug via an ultrasonic apparatus.  
         [0014]    [0014]FIG. 2 is a graph depicting a pulsed ultrasound wave.  
         [0015]    [0015]FIG. 3 is a cross-sectional side view of an ultrasonic drug delivery apparatus.  
         [0016]    [0016]FIG. 4 is a side view of an ultrasonic horn tip with a flat surface tip area.  
         [0017]    [0017]FIG. 5 is a side view of an ultrasonic horn tip with a concave surface tip area  
         [0018]    [0018]FIG. 6A side view of an ultrasonic horn tip with a tip surface having depressions.  
         [0019]    [0019]FIG. 6B is bottom view of the tip surface of FIG. 6A having depressions.  
         [0020]    [0020]FIG. 7 is a cross-sectional side view of an ultrasonic drug delivery applicator.  
         [0021]    [0021]FIG. 7A is a cross-sectional side view of the porous hydrophobic membrane  250 .  
         [0022]    [0022]FIG. 8 is a flow diagram of an in-vivo transdermal and/or intradermal drug delivery method.  
         [0023]    Like reference numbers and designations in the various drawings indicate like elements. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
       [0024]    Referring to FIG. 1, an ultrasonic transdermal and/or intradermal drug delivery apparatus  10  is used to deliver an anti-inflammatory drug to a skin area  20  of a patient&#39;s face  30 , which is affected with acne. The ultrasonic drug delivery apparatus  10  includes an applicator  200  that contains the liquid based anti-inflammatory drug and an ultrasonic transducer  100 . Ultrasonic transducer  100  generates ultrasound waves, which then couple to the applicator  200  and ultimately to the patient&#39;s face  30  through an ultrasonic horn  110 . During the treatment, the bottom surface  204  of the ultrasonic drug delivery applicator  200  is placed in contact with the affected skin area  20  and the ultrasound transducer  100  is turned on for a predetermined time period. The generated ultrasound waves have a predetermined frequency, power and duty cycle. The ultrasound waves cause sonoporation of the skin, as described in the co-pending application entitled “Method of forming micropores in skin” incorporated herein by reference. Sonoporation generates micro-pores in the skin area  20  and a predetermined amount of the anti-inflammatory drug solution is painlessly transported through the micro-pores inside the skin. This procedure is repeated as many times as necessary to cover the total affected skin area and to deliver the total prescribed amount of the anti-inflammatory drug.  
         [0025]    Referring to FIG. 2, in one example, the ultrasound waves are pulses  119  having a frequency of 20 KHz and intensity  119   c  of 20 W/cm 2 . The pulse width  119   a  is 0.5 seconds, the time interval  119   b  between the end of one pulse and the beginning of the next is 9.5 seconds and the period of the ultrasound wave is 10 seconds. In one example, 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.  
         [0026]    Referring to FIG. 3, ultrasonic horn  110  has a first end  112  connected to the ultrasonic transducer  100  and a second end  114  attached to a removable cylindrical tip  400 . Ultrasonic transducer  100  connects via a cable  102  to a power supply  150  that energizes the transducer  100 . The cylindrical tip  400  has a first end  402  with a threaded post  406  and a second end  404 . Threaded post  406  is screwed into threaded hole  120  located at the second end  114  of the ultrasonic horn  110 . Second end  404  of the cylindrical tip  400  has markings  500  indicating the level of the drug solution  300  contained in the applicator  200 . Applicator  200  includes a cylindrical container  205  with a first open end  203  and a second end  204 . Second end  204  is covered with a porous membrane  250 . Membrane  250  has pores  252  with a diameter of a few micrometers, a hydrophobic, non-wettable inside surface  251  and an outside surface  254 , shown in FIG. 7A. Outside surface  254  is covered with a removable protective film  260  that keeps the drug solution  300  contained in the cylindrical applicator container  200 . The ultrasonic horn tip  400  is inserted into the applicator container  200  through the first open end  203 . First and second O-rings,  210  and  220 , respectively, keep the ultrasonic horn tip  400  submerged in the drug solution  300  and prevent leakage of the drug solution  300 .  
         [0027]    Referring to FIG. 4, the tip  400  of the ultrasonic horn  110  includes in addition to the above mentioned threaded post  406  and markings  500 , a first groove  440  and a second groove  460  that accommodate first and second O-rings  210  and  220 , respectively. In one example, the tip  400  is made of titanium and has a length of 10 cm, and a diameter of 1 cm. The bottom surface  410  of the tip  400  is flat and during the time the transducer  100  is on it emits scattered ultrasound waves that cause random micro-poration of the skin.  
         [0028]    In other embodiments the emitted ultrasound waves are focused or parallel. Referring to FIG. 5, an ultrasonic horn tip  400  with a concave bottom surface  410  is used to generate ultrasound waves that focus over a very small skin area. Focused ultrasound waves are used for deep skin micro-poration over a small skin area.  
         [0029]    Referring to FIGS. 6A and 6B, an ultrasonic horn tip  400  with a bottom surface  410  having concave depressions  411  is used to generate parallel ultrasound waves. The overall form and direction of the ultrasound waves depends upon the shape, curvature radius, density and distribution of the depressions  411  across the bottom surface  410 . In the embodiment of FIG. 6B, depressions  411  have the same shape and curvature radius and are uniformly distributed across the bottom surface  410 . In alternative embodiments, the shape, curvature radius, density and distribution of the depressions are varied across the bottom surface  410 . Parallel ultrasound waves are used to generate uniform distribution of micro-pores on the skin surface.  
         [0030]    Referring to FIG. 7, a drug delivery applicator  200  includes a cylindrically shaped hollow container  205  that has an inner wall  201  spaced apart from an outer wall  202  and a wick  270  situated in the space between inner wall  201  and outer wall  202 . The container  205  is preferably made of a transparent hard plastic material and is discarded after use. The wick  270  is made of a highly absorbent and hydrophilic material. In one example, the wick  270  is made of a high-absorbency polyvinyl alcohol sponge (PVA), manufactured by the M-Pact company under the tradename of CLINICEL™. Other examples of highly absorbent and hydrophilic material include HYDROFERA™ PVA sponge manufactured by Hydrofera LLC, Sodium Carboxy-Methyl Cellulose (CMC), blotting paper and any other spongy material. Both the inner and outer applicator walls  201 ,  202  are basically cylindrical and axially aligned, with the exception of two locations on the inner surface  208  of the inner applicator wall  201  where two grooves  212  and  214  are cut out. Grooves  212  and  214  are aligned and placed opposite grooves  440  and  460  cut into the outer surface  408  of the ultrasonic horn tip  400 , respectively. O-rings  210  and  220  occupy the space formed between the oppositely placed grooves  212 ,  440  and  214 ,  460 , respectively. O-rings  210  and  220  facilitate a secure and leak proof fit of the ultrasonic horn tip  400  into the drug delivery applicator  200 .  
         [0031]    Again with reference to FIG. 7, the drug solution inlet septum  230  is located between the outer applicator wall  202  and the inner applicator wall  201  approximately halfway between the open top  203  and bottom surface  204  of the ultrasonic drug delivery applicator  200 . The septum  230  is constructed of a silicon rubber material, designed to be impervious to liquids yet allow injection of the drug solution into the ultrasonic drug delivery applicator  200  using a hypodermic needle.  
         [0032]    Referring to FIG. 7A, porous membrane  250  is attached to the bottom  255  of the inner applicator container wall  201 . Membrane  250  is constructed of a hydrophobic material that resists the passage of the aqueous liquid due to its non-wettable inner surface  251  and has pores  252  with a diameter in range of 10 to 100 micrometers, preferably with diameter of 50 micrometers. In one example, membrane  250  is made of a non-woven polypropylene. The bottom surface  253  of membrane  250  is covered with a removable protective film  260 . In one example, the removable protective film  260  is a thin plastic sheet that is attached to the membrane via a silicon based adhesive  254 .  
         [0033]    In operation, a sterilized ultrasonic drug delivery applicator  200  is placed over the tip of ultrasonic horn  400 . A predetermined drug solution  300  is then introduced into the cylindrical applicator container  205  through the inlet septum  230  via a hypodermic needle (not shown). When the ultrasonic drug delivery applicator  200  is properly filled, the tip of the ultrasonic horn  400  is partially immersed in the solution  300 . Visual inspection of the solution level marking  500  indicates whether the applicator is properly filled, and whether the ultrasonic drug delivery applicator  200  is leaking or defective. Once the ultrasonic drug delivery applicator  200  is filled and determined to be ready for use, the protective film  260  is peeled-off exposing the porous membrane  250 . The apparatus  10  is then placed on the patient&#39;s skin, oriented such that the porous membrane  250  is flush with the skin area where the drugs are to be administered and such that the bottom of the horn tip  410  is immersed in drug solution  300 . A timer (not shown), which is included in the power supply, is set to a pre-determined length of time for sonoporation. The power supply is switched on, and the apparatus sonoporates the skin for an allotted amount of time.  
         [0034]    The membrane  250  resists passage of the aqueous drug solution  300  due to its non-wettable inside surface  251  and the small size diameter pores. A quantity called the breakthrough pressure (P) is used to quantify the hydraulic pressure of the liquid drug that is needed to break through the porous membrane. The breakthrough pressure (P) is described by the following mathematical formula: 
           P =(−4 γ cos ζ)/ D   Equation 1 
         [0035]    Where:  
         [0036]    γ is the surface tension of the liquid,  
         [0037]    ζ is the contact angle formed between the liquid and the smooth surface of the membrane,  
         [0038]    D is the effective pore diameter of the membrane  
         [0039]    When the pressure of the drug solution is less than (−4 γ cos ζ)/D, the drug solution  300  remains contained inside the applicator container  205 . In this case, the purpose of the porous membrane is to prevent the drug solution from leaking prior to transdermal or intradermal infusion process while allowing the ultrasound waves to freely pass through and reach the skin surface  20  and to generate the micro-pores in the stratum corneum. When the pressure of the drug solution  300  is higher than (−4 γ cos ζ)/D, the drug solution  300  passes through the membrane pores and reaches the skin surface  20 , from where it is then transported via the ultrasonic jet pressure through the skin micro-pores into the skin. Excess liquid transferred to the skin during the ultrasound exposure is absorbed by the wicking action of wick  270 . After use, the ultrasonic drug delivery applicator  200  is removed form the ultrasound tip and discarded.  
         [0040]    Referring to FIG. 8, a method  600  of transdermal and/or intradermal drug delivery using the drug delivery applicator of the present invention includes the general steps of preparing the sonoporation apparatus for use, verifying that it is functioning normally, exposing a patient&#39;s skin to ultrasound and administering drugs.  
         [0041]    In particular, in the preparation step, an operator first sterilizes  610  the tip of the ultrasonic horn, then assembles  620  the ultrasonic horn tip with the ultrasonic horn, then attaches  625  the ultrasonic drug delivery applicator (UDDA) to the ultrasonic horn tip and finally injects  630  the drug solution into the UDDA.  
         [0042]    The ultrasonic horn tip  400  may be sterilized using an ethylene oxide gas or by exposing the horn tip  400  to steam. The horn tip may also be pre-sterilized and sealed in a protective package. The sterilized ultrasonic horn tip  400  is attached to the ultrasonic horn  110  by screwing the threaded post  406  of the tip  400  into the threaded hole  120  of the ultrasonic horn  110 . The UDDA is attached to the tip of the ultrasonic horn  400  by inserting the device onto the tip  400 , as described in FIG. 7. The drug solution  300  is injected into the ultrasonic drug delivery applicator  200  via the inlet septum  230  using a syringe.  
         [0043]    In the function verification step  640  the operator compares the level of the drug solution  300  in the ultrasonic drug delivery applicator  200  to the level marking  500  via a visual inspection. If the levels are aligned the operator proceeds with the treatment by first removing the protective film  260  from the ultrasonic drug delivery applicator  200 , then orienting and placing  650  the apparatus on the patient&#39;s skin so that the porous membrane is flush with the skin surface and the tip of the ultrasonic horn  400  is immersed in the drug solution  300 .  
         [0044]    Next the operator administers  670  the drug solution. For this purpose, the ultrasound power is turned on for a predetermined period of time, and ultrasound waves are generated having a frequency, power and duty cycle so that they cause formation of micro-pores in the skin and subsequently transfer the drug from the ultrasonic drug delivery applicator  200  through the skin micro-pores and across the SC into the blood vessels of the blood capillary system. At the end of a successful treatment the power supply is set to a stand-by condition and the UDDA is discarded  690 .  
         [0045]    If in the function verification step  640  the levels are not aligned, the operator proceeds to check  660  via a visual inspection if there are any leaks or defects in the UDDA. If there are no obvious sources of error, the operator adds  680  more drug solution to fill the UDDA to the appropriate level and then checks  640  again the levels. If the UDDA appears to be leaking or is otherwise defective, the operator discards  690  the defective UDDA and repeats step  625 .  
         [0046]    The many features and advantages of the present invention are apparent from the detailed specification, and thus, it is intended by the appended claims to cover all such features and advantages of the described apparatus that follow the true spirit and scope of the invention. Furthermore, since numerous modifications and changes will readily occur to those of skill in the art, it is not desired to limit the invention to the exact construction and operation described herein. Moreover, the process and apparatus of the present invention, like related apparatus and processes used in medical applications tend to be complex in nature and are often best practiced by empirically determining the appropriate values of the operating parameters or by conducting computer simulations to arrive at a best design for a given application. Accordingly, other embodiments are within the scope of the following claims.