WO1998057696A9

WO1998057696A9 - Drug delivery system including a drug transport enhancement mechanism

Info

Publication number: WO1998057696A9
Application number: PCT/US1998/011100
Authority: WO
Inventors: David F Muller
Original assignee: Mile Creek Capital Llc
Priority date: 1997-06-19
Filing date: 1998-06-01
Publication date: 2000-02-17
Also published as: EP0989879A1; AU7804898A; WO1998057696A1; EP0989879A4; CA2294202A1

Abstract

A drug delivery system includes a container (174) in which a shock wave is generated for transmission to a target material, and a drug enhancement mechanism for enhancing absorption of a medicament by the target material. The container (174) includes a shock generating chamber (322), a shock tube (308) coupled to the shock generating chamber (322) having a membrane (310) mounted to a distal end through which the shock wave is transmitted, and a shock wave generating mechanism disposed within the shock generating chamber (322). Illustrative drug enhancement mechanisms include ultrasound, iontophoresis, high-pressure gradients, mechanical vibration, and surfactant. The shock generating mechanism may take various forms, including a rapidly openness divider and electric discharge.

Description

DRUG DELIVERY SYSTEM INCLUDING A DRUG TRANSPORT ENHANCEMENT MECHANISM

BACKGROUND OF THE INVENTION

Various techniques are used to introduce medicinal drugs into a patient's body, including injection and oral administration of medicine in solid or liquid form.

Injection is an effective way to rapidly introduce medicine into a patient's bloodstream. However, patients often experience anxiety and discomfort from injections. Further, infection due to needle contamination is of growing and significant concern.

One type of conventional "needleless" drug injection system includes a mechanism, such as a plunger, by which a narrow stream of medicine is forced out of a nozzle at a very high speed to penetrate the patient's skin. Illustrative "needleless" injection systems are described in U.S. Patent Nos. 5,599,302 (Lilley et al.), 5,383,851 (McKinnon et al.) and 5,064,413 (McKinnon et al.). While such apparatus prevents infection due to needle contamination, injection of the high speed stream can still cause discomfort and anxiety.

While oral administration of medicine is often preferable to injection, this technique suffers certain drawbacks. For example, in some circumstances, manufacture of a drug in a form suitable for oral administration degrades the effectiveness of the drug. Other drawbacks are related to the taste of a liquid medicine, the shape and/or size of a pill or tablet form, and stomach irritation.

Another technique for administering certain medicines is by absorption through the patient's skin (i.e., transdermally). Conventional transdermal drug delivery techniques include the use of ultrasonic energy or other forms of high-frequency energy. For example, in U.S. Patent No. 5,421,816 (Lipkovker), ultrasound energy is used to move a drug through a patient's skin into the bloodstream. In U.S. Patent

No. 5,386,837 (Sterzer), pulse shocks of high-frequency energy, such as RF, microwave, infra-red or laser energy, are employed to create transient pores in the membranes of targeted diseased cells through which drug or chemotherapeutic agents can easily enter the targeted cells. U.S. Patent No. 5,614,502 (Flotte et al.) describes the use of high pressure impulse transients, as may be created by laser-induced ablation, in combination with the administration of certain compounds. The high pressure, laser generated impulse works in combination with the therapeutic compound by generally increasing cell permeability in the region of impulse administration. As used herein, the term "drug delivery" refers to the action by which a drug, medicament, compound, chemical agent, biological agent or the like (collectively, "agents") passes from the outside of cell(s) to the interior of cell(s) to effect a therapeutic, chemical or biological activity. Drug delivery includes transdermal drug delivery, the passage of drugs, compounds and the like through tissue including organs and cell cultures, both in vivo and in vitro. The term "biologic material" encompasses skin, organ tissue, cell cultures and the like.

BRIEF SUMMARY OF THE INVENTION

The invention relates to a drug delivery system including a drug delivery initiator for generating a shock wave and a membrane receiving the shock wave and transmitting the shock wave to a target material. The target material may be the membrane or may be a biologic material, such as a cell or tissue culture, a patient's skin, or a medicament in contact with a biologic material. The drug delivery initiator includes a proximal shock generating chamber and a distal shock delivery tube having a distal end. The membrane is disposed adjacent to, or in contact with, the distal end of the shock tube.

The drug delivery system further includes a shock wave generating mechanism disposed within the shock generating chamber which may take various forms. In one embodiment, the shock wave generating mechanism includes at least one pair of electrodes for generating a shock wave by electric discharge. Alternative shock wave generating mechanisms described herein include a rapidly removable membrane and a piston arrangement.

In the embodiment in which the shock wave generating mechanism includes at least one pair of electrodes, passing an electric current between the electrodes causes a shock wave to be generated and directed through the shock tube. The shock wave is transmitted to the distal end of the initiator to impinge on the membrane which, in turn, transfers the shock wave to the biologic material. Impact of the shock wave on the skin increases the porosity of any of the biomembranes at or below the skin, thereby enhancing absorption of the medicament.

The medicament may be applied to the biologic material in various ways, including direct topical application or through a permeable or rupturable drug containing ampule that is positioned adjacent to the biologic material. In one embodiment, the medicament is topically applied with the use of a penetratable drug containing ampule or drug housing mountable in substantially fluid tight communication to the patient's skin. An optional sealing element provides the fluid tight communication between the drug housing and the patient's skin. To this end, the sealing element includes a cavity having an opening in the bottom surface and at least one piercing element. In use, the drug containing ampule is placed in the cavity of the sealing element and is punctured by the piercing element, causing the medicament to contact the patient's skin through the opening in the sealing element cavity. One embodiment of the sealing element includes straps with which the element is mountable over the patient's skin in the manner of a wrist watch.

The drug delivery initiator may be "closed-ended," with the membrane mounted to the distal end of the shock tube. Alternatively, the initiator may be "open-ended," with the membrane being a separate component or being mounted to, or integrally formed with the drug housing or mounted to, or integrally formed with the sealing element.

In one embodiment, two pairs of electrodes are disposed in the shock generating chamber. A first current passing between one electrode of the first electrode pair and one electrode of the second electrode pair generates a first shock wave and a second current passing between a second electrode of the first and second electrode pairs causes a second shock wave to be generated. The composite shock wave travels through the shock tube to impinge on the membrane.

The drug delivery initiator may be gas and/or liquid impermeable and able to receive a pressurized gas and/or liquid. Use of a pressurized gas or liquid in the initiator permits characteristics of the shock wave, such as rise time and magnitude, to be varied. Suitable gases are rare gases, such as nitrogen and helium, and suitable liquids are ones having a high dielectric breakdown, such as water.

A drug transport enhancement mechanism is described which takes advantage of the increased porosity of the target material achieved with the application of the shock wave, thereby further enhancing absorption of a drug or medicament. The drug transport enhancement mechanism may take various forms, including ultrasound, iontophoresis, mechanical vibration, high pressure gradients, and surfactants and may include apparatus coupled to the drug delivery initiator or provided as a separate unit. Further, the transport enhancement mechanism may be actuated simultaneously with generation and transmission of the shock wave or may be actuated before or after transmission of the shock wave to the target material.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing features of this invention, as well as the invention itself, may be more fully understood from the following description of the drawings in which:

Figure 1 is a cross-sectional view of a transdermal drug delivery system according to the invention;

Figure 2 is a cross-sectional view of an alternate transdermal drug delivery system according to the invention;

Figure 3 is a cross-sectional view of the transdermal drug delivery system of Figure 2 in use; Figure 4 is a cross-sectional view of a further alternate transdermal drug delivery system according to the invention;

Figure 5 is a cross-sectional view of a still further alternate transdermal drug delivery system according to the invention;

Figure 6 an exploded, cross-sectional view of yet another alternate transdermal drug delivery system according to the invention;

Figure 7 is a cross-sectional view of the transdermal drug delivery system of Figure 6 in use;

Figure 8 is an exploded, cross-sectional view of still another transdermal drug delivery system according to the invention; Figure 9 is a cross-sectional view of the transdermal drug delivery system of Figure 8 in use;

Figure 10 is a cross-sectional view of a further alternate transdermal drug delivery system according to the invention;

Figure 11 shows an illustrative circuit for delivering current to the system of Figure 10;

Figure 12 is a cross-sectional view of a still further alternate transdermal drug delivery system according to the invention; and

Figure 13 is a cross- sectional view of an illustrative transdermal drug delivery system including a transport enhancement mechanism.

DETAILED DESCRIPTION OF THE INVENTION

Referring to Figure 1, a shock wave generating system 10 suitable for drug delivery applications includes a shock wave initiator 12 and a shock wave transmission membrane 30. The initiator 12 includes a container 20 having a rapidly openable, or removable divider 24 positioned to separate the container into a first, proximal chamber 28 and a second, distal chamber 32. The proximal chamber 28 is selectively gas impermeable and is able to receive a pressurized gas from an external source (not shown) via a gas port 34. The container 20 communicates with the membrane 30 via an opening 40 at the distal end of the distal chamber 32.

In use, the distal opening 40 of the container 20 is brought into shock wave communication with the membrane 30 which is further brought into shock wave communication with a target material 14. The target material may be a biologic material, such as a patient's skin, or a medicament in contact with a biologic material. Rapid opening, or removal of the divider 24 causes a shock wave to be generated upon the release of pressurized gas from the proximal chamber 28 to the distal chamber 32. The shock wave travels through the distal opening 40 to impinge on the membrane 30 which transfers the shock wave to the biologic material 14.

The shock wave is a high-pressure wave propagating at supersonic speeds, with a typical rise time on the order of one to one-hundred nanoseconds and a useful duration on the order of several hundred nanoseconds, following which the shock wave dissipates significantly. Typical shock wave magnitudes are characterized by a pressure on the order of between one and five-hundred barrs.

The delivery apparatus and techniques described herein are suitable for transmitting shock waves to various biological materials to enhance absorption of various compounds, medicaments and other agents by the biologic material. For simplicity of illustration, the apparatus and techniques are described herein primarily with reference to transdermal drug delivery, with the biologic material 14 being a patient's skin. Other applications for the shock wave generating systems described herein include in vitro applications to effect absorption of such agents by cell cultures, and other in vivo applications, including gene therapy, invasive surgery and/or delivery of agents through forms of organs, tissue and physiological systems other than skin.

Impact of the shock wave on the biologic material (e.g., patient's skin) causes the porosity of the biologic material (i.e., the permeability of the cells) to increase temporarily, thereby enhancing absorption of the agent (i.e. , diffusion of the agent through the cell wall). Typically, the shock wave propagates through the biologic material (e.g., patient's skin) to a depth on the order of a few centimeters before significant dispersion occurs.

The extent to which the cell porosity is increased can be manipulated by varying the rise time and magnitude of the generated shock waves. In general, the rise time and magnitude of the shock waves are selected to ensure that the permeability of the skin 14 is optimally affected, without destroying the viability of the target cells. As one example, the cell permeability is affected for a duration of between several seconds and several minutes and the temporary permeability increase is sufficient to permit a variety of medicinal compounds and other agents, with a wide range of molecular weights, to enter the cells. It is believed that the molecular weights of agents useful with the system of the invention ranges from about 100 kilodaltons to several thousand kilodaltons. It will be appreciated by those of ordinary skill in the art that various factors, other than the rise time and magnitude of the shock wave, affect the absorption of the medicament by the skin, including electrostatic forces between cell membranes, the form, type and amount of the compound and the pH level. The patient's skin can be prepared for shock wave application by treatment with a medicament. The medicament may be administered either locally or systemically, by various conventional pharmaceutical techniques. For example, the medicament may be applied topically or internally (i.e., orally or with an injection, such as an intravenous, intramuscular or intradermal injection). Further, the sequence of applying a drug and a shock wave to a target material may be varied. That is, the drug may be applied before, during and/or after application of the shock wave to the target material.

As one example, direct topical application may be performed prior to shock wave treatment, such as by spreading the compound over a localized region of the skin targeted for subsequent shock wave treatment. In some applications, it may be advantageous to wait a predetermined amount of time after application of the medicament and before shock wave application, in order to permit dispersion of the medicament. Alternatively, the compound may be present within a drug-containing ampule which is applied to the skin during and subjected to shock wave treatment, with the use of a drug housing, as described in conjunction with Figures 6-9. As a further example, a transdermal patch may be used to apply the medicament to the target material. The patch may be applied before application of the shock wave and thus, be subject to the shock wave or, alternatively the patch may be applied after application of the shock wave to the target material.

In many applications, it is advantageous to apply the medicament to the body internally (i.e. , orally or with an injection, such as an intravenous, intramuscular or intradermal injection). Application of shock waves to the skin following injection of an agent into the body renders the body more amenable to the effects of the agent. In some applications, it is advantageous to administer the agent such that the level of the agent in the surrounding tissue is less than fifty percent of the level of the agent in the target tissue. Thus, compounds are applied in a way that produces greater concentrations in the target material than in the surrounding area and compounds which are taken up in greater amounts and/or retained substantially longer in the target tissue relative to the surrounding tissue are preferred. Specifically, advantageous compounds include antibiotics, cytotoxic compounds, light activated dyes and salicylates.

The container 20 may take various forms, in terms of its size and shape. Ideally, the size of the container 20 has a height on the order of six to eight inches long, with a diameter on the order of one to two inches, with the height of the proximal chamber 28 being approximately four times greater than the height of the distal chamber 32. Generally, the container 20 is comprised of a material having suitable strength and gas impermeability characteristics. Exemplary materials for providing the container 34 include metals and metal alloys, such as stainless steel, copper and aluminum, and various polymeric materials.

In the illustrative embodiment, the container 20 is tapered so as to have a slightly smaller diameter at its distal end than at its proximal end and the opening 40 is substantially circular in shape. It will be appreciated by those of ordinary skill in the art that the particular size and shape of the container 20 and its features, including the distal opening 40, can be readily modified suit a particular application. As one example, the size of the distal opening 40 may be decreased in order to focus the shock waves transmitted therethrough.

The rapidly openable divider 24 may take various forms, including a rupturable, gas impermeable diaphragm as shown in Figure 1 or a valve as is shown in Figure 5. In the case of a rupturable diaphragm providing the divider 24, the diaphragm is removably and replaceably mounted within the container 20, such as with the use of mounting brackets 46 fastened to, or integrally formed with the inner wall of the container 20.

Suitable materials for providing the gas impermeable diaphragm 24 include metals, such as titanium, titanium alloys, aluminum, tin, stainless steel and copper and polymeric materials, such as polyaramid fibers, polyamides, cellulose, cellulose acetate, polyvinyl chloride, polyester and mylar. The diaphragm 24 may be self-rupturable in response to the pressure differential across it exceeding a predetermined magnitude (i.e., the "rupture point"). Further, the gas impermeable diaphragm 24 may be scored and the rupture point may be varied by varying the scoring pattern and/or extent.

Alternatively, the diaphragm 24 may be rupturable in response to an external force, such as an electric charge, heat or a mechanical action.

The shock wave transmission membrane 30 is deflectable in response to shock wave impact. However, the extent of deflection may be so small as to be undetectable by the naked eye and/or negligible. Suitable materials for fabricating the membrane

30 include metals, such as titanium, titanium alloys, aluminum, tin, stainless steel, molybdenum and copper and polymers, such as polyaramid fibers, polyamides, cellulose, cellulose acetate, polyvinyl chloride, polyester and mylar.

The membrane 30 may be gas impermeable or alternatively, may be gas permeable. A gas permeable membrane may include one or more perforations, preferably having a relatively small size as compared to the surface area of the membrane 30 and, more preferably, having a size on the order of 0.1 to 1.0 millimeters. The gas flowing through a gas permeable membrane works in conjunction with the force of the shock wave, albeit over a much longer time constant than the shock wave, to force the medicament into the patient's skin. While the shock wave lasts on the order of several hundred nanoseconds before dissipating significantly, the impact of gas from the distal chamber passing through the membrane 30 and to the medicament and patient's skin 14 continues for a duration on the order of milliseconds.

Thus, once the shock wave has dissipated, the gas movement through the membrane

30 serves to provide additional force on the medicament and the patient's skin 14, thereby improving absorption of the medicament.

The membrane 30 may be part of various components of the drug delivery system 10. For example, in the embodiment of Figure 1, the membrane 30 is a separate component. Alternatively, the membrane may be mounted to the container 20 as shown in Figure 2, may be part of an optional drug housing as shown in Figure 3 or may be part of a sealing element as shown in Figure 6.

In use, the distal chamber 32 of the container 20 is initially filled with a gas, at a predetermined pressure, and the proximal chamber 28 receives a pressurized gas via the gas port 34. In the illustrative embodiment, the distal chamber 32 is filled with air at ambient atmospheric pressure. Many pressurized gases are suitable for introduction into the proximal chamber 28, including carbon dioxide, hydrogen, argon, nitrogen, air and rare gases, including helium, argon, neon and xenon.

In the case where the divider 24 is a self-rupturable diaphragm, as gas is being pumped into the proximal chamber and when the pressure differential between the proximal and distal chambers 28, 32, respectively, reaches a predetermined magnitude, the diaphragm 24 ruptures. This rapid opening of the divider 24 causes a shock wave to be generated and transmitted into the distal chamber 32. The shock wave travels through the opening 40 at the distal end of the chamber 32 and impinges on the adjacent membrane 30 which, in turn, transmits the shock waves to the patient's medicament-treated skin 14. Impact of the shock waves on the patient's skin 14 causes the porosity of the skin cells to increase temporarily, as described above. A release valve 18 in the wall of the proximal chamber 28 permits any gas remaining in the container 20 after shock wave generation to be purged. In this way, the proximal chamber 28 of the initiator container 20 is readied to accept pressurized gas for reuse.

With this arrangement, an effective drug delivery system is provided using an apparatus which is relatively simple and inexpensive. In this way, the advantages of transdermal drug delivery, as compared to injections and oral administration, are realized, without the drawbacks associated with complex and expensive equipment, such as ultrasonic and/or laser equipment.

The shock wave generating system 10 of Figure 1 can be characterized as "open-ended" in the sense that the container 20 has an opening 40 at its distal end.

Figure 2 shows a "closed-ended" shock wave generating system 50 suitable for transdermal drug delivery, with like reference characters referring to like elements. In the embodiment of Figure 2, the membrane 30 is mounted to the container 20, at the distal end of the distal chamber 32. More particularly, the membrane 30 is mounted to the container so as to cover the opening 40 at the distal end and, thus, to close the container, as shown, and may be mounted with a gas tight seal.

The system 50 includes container 20 in which the rapidly openable divider 24 is disposed to divide the container into the proximal chamber 28 and the distal chamber 32, as described above in conjunction with Figure 1. The gas port 34 permits introduction of a pressurized gas into the distal chamber 28 from an external gas source

(not shown).

Referring to Figure 3, use of the closed-ended shock wave generating system 50 is illustrated, with the container 20 brought into shock wave communication with the patient's skin 14 for generation and transmission of shock waves to the patient's skin 14 upon the rapid opening of the divider 24. More particularly, in the illustrated application, the container 20 is brought into contact with a medicament, or drug 54 suitable for absorption by the skin 14.

The medicament 54 may be provided in various forms in accordance with the various manners by which the skin is treated. As examples, the medicament 54 may be a liquid, gel, ointment or creme which is applied topically to the patient's skin 14. Alternatively, the medicament 54 may be contained in a penetratable drug housing, as in the embodiments of Figures 6-9, or a drug housing which is permeable to the drug.

Referring to Figure 4, a shock wave generating system 60 includes an alternative mechanism for introducing pressurized gas into the proximal chamber. The shock wave generating system 60, like the above-described embodiments, includes an initiator 62 comprising a container 64 in which a rapidly openable divider 66 is disposed to separate the container 64 into a first, proximal chamber 68 and a second, distal chamber 70 having an opening at the distal end. The system 60 of Figure 4 is closed- ended in the sense that the shock wave transmission membrane 74 is mounted to the container 64 at the distal end so as to cover the distal opening 76 and is operative in the same manner as described above to generate and transfer shock waves through the membrane 74 to the medicament 54 and patient's skin 14.

A pressurized gas cartridge 80 is removably and replaceably disposed in the proximal chamber 68. In order to facilitate removal and replacement of the cartridge 80 for subsequent use of the shock wave generating system 60, the container 64 is provided with a removable cover 88 which is designed to maintain the gas impermeability of the container 64, such as with the use of a rubber gasket. A release valve 72 is disposed through the cover 88 in order to permit any gas remaining in the container 64 after use to be purged.

A mounting bracket, or frame 84 is provided for securing the cartridge 80 within the proximal chamber 68. It will be appreciated by those of ordinary skill in the art, however, that various techniques are suitable for mounting the cartridge 80 within the proximal chamber 68. An actuator 86 accessible from the exterior of the container 64 permits the pressurized gas cartridge 80 to be punctured upon actuation, thereby releasing the pressurized gas into the proximal chamber 68. Release of the pressurized gas into the proximal chamber 68 causes the pressure differential across the diaphragm

66 to exceed its "rupture point." The rupturing of the diaphragm 66 causes shock waves to be generated and transmitted through the distal chamber 70 and membrane 74 in the manner described above.

The actuator 86 may take various forms. In the illustrative embodiment, the actuator 86 is a lever having a handle 90 and a puncturing element 94. In use, moving the handle 90 toward the proximal end of the container 64 causes the puncturing element 94 to move into contact with, and puncture the mouth 82 of the cartridge 80. It will be appreciated by those of ordinary skill of the art that various mechanical mechanisms, other than the illustrated puncturing element 94, are suitable for puncturing the pressurized gas cartridge 80. Further, the cartridge 80 may be punctured by other means.

Referring to Figure 5, a closed-ended shock wave generating system 100 including an initiator 102 for transmitting shock waves to a patient's skin 14 includes a rapidly openable divider 108 in the form of a valve. The valve 108 is disposed in a container 104 of the initiator 102 so as to divide the container 104 into a first, proximal chamber 110 and a second, distal chamber 112 having a membrane 114 mounted over an opening at the distal end. A gas port 116 permits pressurized gas to be introduced into the proximal chamber 110 from an external source (not shown) and a release valve

106 permits gas remaining in the container 104 after use to be purged, thereby readying the system 100 for subsequent use. The valve 108 includes a sliding portion 118 which is movable by an actuator

120 between a first, closed position (shown by dotted lines) in which the sliding portion

118 abuts a stop 124 and a second, open position (shown by solid lines) in which the sliding portion 118 is spaced from the stop 124. With the sliding portion 118 of the valve in the closed position, the valve provides a gas impermeable seal between the proximal chamber 110 and the distal chamber 112.

Actuation of the valve 108 via actuator 120 causes very rapid movement of the sliding portion 118 from the first, closed position to the second, open position. It is this rapid opening of the valve which causes a shock wave to be generated and transmitted through the distal chamber 112 to impact the shock wave transmission membrane 114, medicament 54 and skin 14 in the manner described above. The actuator 120 may take various forms, such as an electric circuit, a mechanical actuator, or an electromechanical actuator. Further, it will be appreciated by those of ordinary skill in the art that while the illustrated valve 108 is relatively simple in design, more elaborate valves, such as gate valves or piston-based valves may be used.

Referring to Figure 6, an alternate transdermal drug delivery system 130 includes a closed-ended shock wave initiator 134 of the type described above in conjunction with Figure 2, a drug housing 136 and a sealing element 140. The drug housing 136 is adapted for containing a medicament and includes a first surface 138 adapted for being penetrated to permit the medicament to flow towards the patient's skin 156 and a second, opposite surface 168.

The shock wave initiator 134 includes a container 128 in which a rapidly openable divider 142 in the form of a rupturable diaphragm is mounted so as to divide the container into a first, proximal chamber 144 and a second, distal chamber 146 having an opening 148 at the distal end thereof. A shock wave transmission membrane

150 is mounted to the container 128 so as to cover the opening 148 at the distal end of the chamber 146. A gas port 152 permits a pressurized gas to be introduced into the first chamber 144 from an external source (not shown) and a release valve 154 permits gas remaining in the container 128 after use to be purged. The sealing element 140 is mountable to the patient's skin 156 and is adapted for receiving the drug housing 136 and providing a fluid tight seal between the drug housing 136 and the patient's skin 156. To this end, the sealing element 140 includes a cavity 160 sized and shaped to receive the drug housing 136 and having an opening 166 in the bottom surface 144 for permitting the medicament to contact the patient's skin 156. The sealing element 140 further includes a mechanism for mating with the container 128. In the illustrative embodiment, screw threads 162 disposed in the sealing element cavity 160 are mateable with complimentary screw threads 164 disposed around the distal end of the container 128. It will be appreciated by those of ordinary skill in the art that various mechanisms may be used for mating the sealing element 140 and the container 128, such as a Luer lock.

The sealing element 140 includes a mechanism for penetrating the surface 138 of the drug housing 136, thereby causing the medicament to flow through the opening 166 toward the patient's skin 156. In the illustrative embodiment, piercing elements 146 project upward from the cavity 160 of the sealing element so as to puncture the surface 138 of the drug housing. In the illustrative embodiment, the sealing element 140 includes a straps 158 which permit the element to be worn by the patient in the manner of a wrist watch. It will be appreciated by those of ordinary skill in the art however that the sealing element 140 may take various forms.

The drug housing 136 may be comprised of various materials and the size and shape of the housing 136 may be readily varied to suit a particular application and sealing element 140, as will become apparent. For example, the drug housing may be adapted to mate with the drug delivery initiator container 128 as shown in Figure 8. As another example, the drug housing 136 may not require puncturing, but rather may be permeable to the medicament or may be ruptured by impact of the shock waves. Referring also to Figure 7, the transdermal drug delivery system 130 is shown in assembly, prior to shock wave generation. The drug housing 136 is disposed within the cavity 160 of the sealing element 140 and the bottom surface 138 of the drug housing has been penetrated by piercing elements 146. The shock wave initiator container 128 is brought into shock wave communication with the drug housing 136 and the patient's skin 156 by mating the distal end of the container chamber 146 with the mateable portion 162 of the sealing element 140. More particularly, the container 128 is placed over the sealing element 140 and is screwed down so that the screw threads 164 of the initiator container 128 engaged the screw threads 162 of the sealing element 140. With the system 130 disposed as shown in Figure 7, a pressurized gas is introduced into the first chamber 144 via the gas port 152 for rupturing the diaphragm

142 as described above in order to generate a shock wave for transmission to the patient's skin 156.

A further alternate transdermal drug delivery system 170 is shown in Figure 8, with like numerals referring to like elements. In the system 170, the drug delivery container 174 is mateable to a drug housing 176 and the shock wave transmission membrane is provided as part of the drug housing 176. More particularly, the initiator container 174 is open-ended and includes a rapidly openable divider 180 mounted to divide the initiator container 174 into a proximal chamber 182 and a distal chamber 184, as shown. A gas port 186 permits communication of an external source (not shown) of pressurized gas with the proximal chamber 182 and a release valve 198 permits gas remaining in the container 174 after use to be purged. The distal chamber

184 terminates at a mating portion 188 which defines an opening 190 at the distal end. In the illustrative embodiment, the mating portion 188 includes screw threads.

The drug housing 176 is adapted for containing a medicament and has a first surface 192 adapted for being punctured or otherwise opened to release the medicament and a second, opposite surface 194. The drug housing 176 further includes a mating portion 196 suitable for mating to portion 188 of the initiator container 174. The second surface 194 of the drug housing 176 provides the shock wave transmission membrane (like membrane 150 in Figure 6, for example). This membrane 194 may be integrally formed with the drug housing 176 or, alternatively, may be a separate component positioned over the surface of the drug housing 176.

A sealing element 200 is provided for receiving the drug housing 176 and for affecting a fluid tight seal between the drug housing and the patient's skin 204. The sealing element 200 is substantially similar to sealing element 140 (Figures 6 and 7), with the exception that the sealing element 200 does not include mating portion 162. This is because the initiator container 174 mates with the drug housing 176 as opposed to mating with the sealing element 200. The sealing element 200 thus includes a cavity 206 which is adapted for receiving the drug housing 176 and in which piercing elements 208 are disposed for piercing the first surface 192 of the drug housing. An opening 212 in the bottom surface 214 of the sealing element permits the medicament to flow toward the patient's skin. The illustrative sealing element 200, like sealing element

140, includes straps 210 to permit the sealing element to be worn by the patient in the manner of a wrist watch.

Referring to Figure 9, the transdermal drug delivery system 170 is shown placed over the patient's skin 204 and ready for use. The drug housing 176 is positioned within the cavity 206 of the sealing element 200, with the first surface 192 of the drug housing penetrated by the piercing elements 208. Thus, the medicament contacts the patient's skin 204 via the opening 212 within the sealing element 200. The drug delivery initiator container 174 is brought into engagement with the drug housing 176, with the threaded portion 188 of the container mated with the threaded portion 196 of the drug housing. With the system 170 thus positioned, the container 174 is ready to receive a pressurized gas via the gas port 186. Rapid rupture of the diaphragm 180 due to a predetermined pressure differential between the proximal chamber 182 and the distal chamber 184 causes a shock wave to be created and transmitted through the distal chamber 184, distal opening 190 and drug housing 176 to impinge on the patient's skin 204. One of ordinary skill in the art will appreciate that the container 20 may be altered in size and shape to be useful in applications other than transdermal drug delivery. As examples, the distal chamber 31 may be comprised of a flexible material and/or system can be dimensioned to be used with or in a catheter to be useful in minimally invasive surgical techniques (e.g., endoscopic surgery) or open surgery. Referring to Figure 10, an alternate transdermal drug delivery system 300 comprising a drug delivery initiator 316 and a shock wave transmission membrane 310 delivers shock waves to a target material, such as a patient's skin, disposed adjacent to a distal end 304 of a shock delivery tube 308 in response to an electric discharge. The shock wave transmission membrane 310 is disposed at, or adjacent to, the end 304 of the tube 308 and may be mounted to the tube end 304 or may be placed in direct contact with the biologic material or with a drug housing containing a medicament, as described above. The system 300 of Figure 10 further includes a drug transport enhancement mechanism 36 which will be described further in conjunction with Figure 13. The membrane 310 is provided as described above in conjunction with membrane 30 (Figure 1). That is, the membrane 310 is deflectable in response to shock wave impact, but the extent of deflection may be so small as to be undetectable by the naked eye and/or negligible. Suitable materials for fabricating the membrane 310 include metals, such as titanium, titanium alloys, aluminum, tin, stainless steel, molybdenum and copper and polymers, such as polyaramid fibers, polyamides, cellulose, cellulose acetate, polyvinyl chloride, and polyester. Further, the membrane 30 may be gas impermeable or gas permeable, but preferably, is gas impermeable.

The drug delivery initiator 316 includes a shock generating chamber 322 and the shock tube 308 coupled to and extending from the chamber 322 to terminate at the distal end 304. The shock generating chamber 322 has a mechanical coupling 318 at a proximal end 320 which is adapted for mating with a cable 324 through which an electrical current is provided to the system 300. In the illustrated embodiment, the cable 324 is a fifty kilovolt insulated cable having a screw thread connector 326 which is matable with the coupling 318 of the chamber 322. However, it will be appreciated by those of ordinary skill in the art that alternative types of mechanical couplings are possible and are within the spirit and scope of the invention.

The shock wave generating chamber 322 houses at least one pair of electrodes 334a, 334b mounted to an electrode support 336. The electrode support 336 is a conductive member attached to a rigid extension 328 of the cable 324 and electrically connected to the center conductor of the cable. In the illustrative embodiment, the electrode support 336 has a substantially concave shape, as shown. While other shapes for the electrode support 336 are possible, the concave shape advantageously assists in focusing the current, and thus improves the reproducibility of the device.

A second pair of electrodes 340a, 340b may also be housed within the shock wave generating chamber 322 in juxtaposition to the first electrode pair 334a, 334b, respectively, as shown. The electrodes 340a, 340b are supported by respective, elongated electrode support members 344a, 344b which are coupled to the wall 348 of the chamber 322 by any suitable mechanism.

In use, a user actuatable switch (Figure 11) is actuated to cause an electrical current to be provided to the electrodes 334a, 334b via the cable 324 and the conductive electrode support 336. The electrical current thus provided passes between electrode 334a and electrode 340a, as well as between electrode 334b and electrode 340b. The electrodes 340a, 340b, which are mechanically and electrically coupled to the chamber wall 348, provide a return path for the current. Each of the two currents causes a respective shock wave to be generated having a wavefront which is substantially orthogonal with respect to the current path. The resulting shock waves combine to generate a composite shock wave which has a wavefront oriented orthogonally with respect to the elongated axis of the delivery tube 308, resulting in the shock wave traveling along the elongated axis of the tube 308. With this arrangement, a shock wave is delivered to the membrane 310 for transfer to the target.

The characteristics of the shock wave thus produced, including magnitude and rise time, can be varied by varying the level of the current passed between the electrode pairs and/or by introducing a gas or liquid into the initiator 316. Suitable gases include rare gases, such as nitrogen and helium. Suitable liquids include water and other liquids having a high dielectric breakdown characteristic. The gas or liquid thus introduced establishes different pressures within the initiator 316 and thus different shocks produced by the electric current.

Each of the electrodes 334a, 334b and 340a, 340b is comprised of a conductive material having strength characteristics suitable for withstanding the shock waves generated in the system 300. Suitable materials include steel, titanium, tungsten, and carbon. Similarly, the drug delivery initiator 316 may be comprised of various materials having strength characteristics suitable for withstanding the generated shock waves. In the illustrative embodiment, the initiator 316 is comprised of stainless steel. Alternative suitable materials for the initiator 316 include steel, titanium, tungsten, and carbon.

The drug delivery initiator 316 may be a unitary structure or, alternatively, may be comprised of more than one element assembled together for use, as shown in the embodiment of Figure 10. In particular, the initiator 316 includes a back plate 350 on which the mechanical coupling 318 is provided and a forward section 354 having a flange 356 suitable for mating with the back plate 350. In the illustrative embodiment, the forward section 354 is unitarily formed with the shock wave delivery tube 308. Various mechanisms are suitable for securing the back plate 350 to the flange 356, including the use of screws, as shown. The interface between the back plate 350 and the forward section 354 may include one or more gaskets or other gas and/or liquid sealing mechanisms.

An inlet/outlet port 360 provides access to the shock wave generating chamber 322 through a valve 364. The tube 360 may be used to introduce pressurized gas and/or liquid into the chamber 322 and/or to purge the chamber 322 between uses. It will be appreciated by those of ordinary skill in the art that while the embodiment of Figure 10 utilizes two electrode pairs, each of which generates a shock wave which combine to provide the composite shock wave which travels along the elongated axis of the tube 308,. a more simple, single electrode pair arrangement may be used. In this case, the two electrodes of the single electrode pair would be disposed along an axis substantially orthogonal to the elongated axis of the shock tube 308 in order to generate a shock wave for transmission along the length of the tube. As one particular example, the electrodes 334a, 334b may be eliminated and a single current passed between electrodes 340a and 340b. As a further alternative, more than two electrode pairs may be used to generate a shock wave for delivery through the tube

308.

Referring to Figure 11, an electrical circuit 370 for use with the system 300 of Figure 10 to generate the current provided through the cable 324 is shown. The circuit 370 includes a user actuatable switch 374 which, when actuated, couples a supply voltage, such as 110 volts AC, to the circuit. Actuation of the switch 374 causes a relay 378 to close and a current to be provided through a first, pulse transformer 376 and a second transformer 382.

The current through the pulse transformer 376 activates a high voltage/high current switch 380, such as a Thyrotron or silicon controlled rectifier (SCR). Firing of the switch 380 causes a current to be provided to the electrodes 334a, 334b via the cable 324.

Referring to Figure 12, an alternate transdermal drug delivery system 400 includes a drug delivery initiator 402 comprising a shock generating chamber 404 and a shock tube 406 coupled to and extending from the chamber 404. Like the previously described embodiment, a distal end 408 of the shock tube 406 is in shock wave communication with a membrane 410 which is adapted for being disposed adjacent to a target material, e.g., a patient's skin, which is either in contact with the skin or with a drug housing containing a medicament. The membrane 410 may or may not be attached to the distal end 408 of the shock tube 406 (i.e., the initiator 402 may be either open or closed ended), but preferably is closed ended.

The system 400 of Figure 12 generates a shock wave in response to actuation of a "piston-type" valve arrangement housed within the chamber 404. The piston 412 includes an end cap 432 of the shock tube 406 and a member 434, which elements are secured together to move relative to the shock tube 406 and the chamber 404. More particularly, a back plate 414 separates the chamber 404 into a rear chamber 416 and a forward chamber 418 in which the shock tube end cap 432 is disposed.

In use, the piston 412 is positioned as shown, with the end cap 432 covering a proximal end 422 of the shock tube 406 as the rear chamber 416 is filed with a pressurized gas. When the rear chamber 416 is vented to a lower pressure, such as atmospheric pressure, the piston elements 432, 434 move rapidly toward a rear flange 428 of the chamber. This rapid movement of the piston 412 causes a shock wave to be generated having a wavefront orthogonal to the elongated axis of the shock tube 406, such that the shock wave travels along the elongated axis of the shock tube toward the membrane 410.

The drug delivery initiator 402 includes several inlet and outlet ports for introducing gases and/or liquids into the chamber 404 and shock tube 406 and for evacuating the chamber and shock tube between uses. The gas handling system of the initiator 402 is described in a paper entitled A piston-actuated shock-tube, with laser- Schlieren diagnostics, S. M. Hurst and S. H. Bauer, Rev. Sci. Instrum., Vol. 64, No. 5, May 1993, which paper is incorporated herein by reference. The initiator 402 may be comprised of various materials exhibiting suitable strength characteristics to withstand the shock waves generated therein, such as steel. Likewise, the shock tube 406 may be comprised of various materials, including steel. Alternatively, certain components, such as the back plate 414, may be comprised of plastic. As with the previously described embodiments, the drug delivery initiator 402 may be a unitary structure or, alternatively, may be comprised of more than one element assembled together for use.

Referring to Figure 13, an illustrative shock wave generating system 50' includes a drug transport enhancement mechanism 36 for enhancing the absorption of a medicament into a patient's skin, beyond the increased absorption caused by a shock wave. That is, the transport enhancement mechanism 36 takes advantage of the increased porosity of the patient's skin achieved with the application of a shock wave transmitted through any of the shock wave generating systems described herein. The transport enhancement mechanism 36 may take various forms and may be provided in conjunction with any of the shock wave generating systems described herein.

The transport enhancement mechanism 36 may include an apparatus provided as a separate unit from the shock wave initiator which is moved into alignment with the target material and actuated after delivery of the shock wave. Alternatively, the transport enhancement mechanism 36 may include an apparatus which is coupled to the shock wave initiator and actuated during delivery of the shock wave.

In one embodiment, the transport enhancement mechanism 36 is a pressure generating unit which is operative to exert additional pressure on the target (e.g. , the patient's skin) in the manner of the gas permeable membrane described above in conjunction with Figure 1, to work in conjunction with the force of the shock wave, but over a longer time constant, to force the medicament into the skin. Such a pressure generating unit may be used to apply a high pressure liquid or gas to the patient's skin, for example, through a hose or nozzle directed to the target material.

Alternative suitable types of drug transport enhancement mechanisms include: ultrasound, iontophoresis, mechanical vibration, surfactants and laser energy. For example, in the case of surfactants as a drug transport mechanism, a surfactant, such as soap, may be mixed with a medicament or may be applied after application of the medicament to the patient's skin in order to maintain the porosity of the skin which has been increased by application of a shock wave. One suitable type of iontophoretic device includes a patch which contains two reservoirs on its bottom surface which, in use, are in contact with the skin. One such reservoir contains a drug and both reservoirs contain an electrode. In use, an electric current passes between the electrodes, with the drug being a carrier of the charge and passing through the skin where it is absorbed.

The use of laser energy as a drug transport enhancement mechanism is particularly well suited for drug, or chemical application to hair follicles, such as may be useful in hair removal applications. In this example, the medicament delivered to a patient's skin may be a chemical that absorbs laser energy at a predetermined wavelength. Once the drug delivery apparatus is actuated, the chemical is delivered through the skin to subdermal structures such as hair follicles. Laser energy is subsequently applied to the skin and efficiently delivered to the hair follicles due to the presence of the chemical absorber to remove hair.

As noted above, the drug or medicament may be applied to the patient's skin by a variety of techniques, such as direct topical application or through a permeable or rupturable drug containing ampule, or a patch that is positioned adjacent to the biologic material.

Having described the preferred embodiments of the invention, it will now become apparent to one of ordinary skill in the art that other embodiments incorporating their concepts may be used. For example, it will be appreciated by those of ordinary skill in the art that various phenomena, in addition to shock waves, may be utilized to increase the porosity of a biologic material so as to enhance medicament absorption, such as electrical discharge, laser ablation, piezoelectric devicestherefore that these embodiments should not be limited to disclosed embodiments but rather should be limited only by the spirit and scope of the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety.

Claims

What is claimed is:

1. A drug delivery system, comprising: a drug housing having a medicament receiving chamber with a first, open end mountable in fluid tight communication with a biologic material and a second end; and a drug delivery initiator comprising: a shock generating chamber; a shock tube having a proximal end coupled to the shock generating chamber and a distal end; a membrane mounted to the distal end of the shock tube; and at least one pair of electrodes disposed within the shock generating chamber and adapted for passing an electric current therebetween in order to generate a shock wave directed through said shock tube.

2. The system of claim 1 wherein the membrane is made from a metal selected from the group consisting of titanium, titanium alloys, aluminum, tin, stainless steel, molybdenum and copper.

3. The system of claim 1 wherein the membrane is made from a polymer selected from the group consisting of polyaramid fibers, polyamides, cellulose, cellulose acetate, polyvinyl chloride, and polyester.

4. The system of claim 1 wherein the distal end of the shock tube is selectively matable with the drug housing.

5. The system of claim 1 further comprising a sealing element effective to create the fluid tight communication between the biologic material and the first end of the drug housing.

6. The system of claim 5 wherein the distal end of the shock tube is selectively matable with the sealing element.

7. The system of claim 1 wherein the at least one pair of electrodes is disposed along an axis substantially orthogonal to an elongated axis of the shock tube.

8. The system of claim 1 further comprising a second pair of electrodes, wherein a first current is passed between a first one of the first pair of electrodes and a first one of the second pair of electrodes and a second current is passed between a second one of the first pair of electrodes and a second one of the second pair of electrodes.

9. The system of claim 1 wherein the shock generating chamber is gas impermeable and able to receive a pressurized gas.

10. The system of claim 9 wherein the pressurized gas is selected from the group consisting of rare gases, including helium, argon, neon and xenon.

11. The system of claim 1 wherein the shock generating chamber is liquid impermeable and able to receive a pressurized liquid.

12. The system of claim 11 wherein the liquid is water.

13. The system of claim 1 wherein said drug delivery initiator further comprises a cable coupled to said shock generating chamber for delivering said electric current to said at least one pair of electrodes.

14. The system of claim 13 wherein said at least one pair of electrodes is supported by an electrode support disposed at an end of said cable inside said shock generating chamber.

15. The system of claim 1 wherein the medicament is in a form selected from the group consisting of a gel and a liquid.

16. A shock wave generating system, comprising: a container; a rapidly openable valve disposed within said container and adapted to move within said container; and a shock tube coupled to said container through which a shock wave is transmitted to a target material upon actuation of said valve within said container.

17. The system of claim 16 wherein said valve is provided in the form of a piston.

18. The system of claim 17 wherein said container has at least one port adapted for permitting a pressurized gas to be introduced into the container.

19. The system of claim 18 wherein the at least one port is adapted for permitting the pressure within the container to be rapidly decreased to cause said piston to move.

20. The system of claim 16 wherein the shock tube has at least one port adapted for permitting a pressurized gas to be introduced into said shock tube.

21. A drug delivery system, comprising: a container; a rapidly openable valve disposed within said container and adapted to move within said container; and a shock tube coupled to said container through which a shock wave is transmitted to a target material for application of a drug to the target material upon said piston moving within said container.

22. The drug delivery system of claim 21 wherein the valve is provided in the form of a piston.

23. A shock wave generating system, comprising: a container having proximal and distal ends; and at least a pair of electrodes disposed within the container, wherein said distal end of said container has an opening at the distal end through which a shock wave is transmitted to a target material upon an electric current being passed between said at least one pair of electrodes.

24. The system of claim 23 wherein the target material is a biologic material.

25. The system of claim 23 wherein the target material is a medicament in contact with a biologic material.

26. The system of claim 23 further comprising a membrane having a first surface that receives the shock wave generated upon said electric current passing between said at least one pair of electrodes, and a second, opposed surface that transmits the shock wave received by the first surface.

27. The system of claim 26 wherein the membrane is affixed to the opening at the distal end of the container.

28. The system of claim 27 wherein the membrane is affixed to the opening at the distal end of the container with a gas tight seal.

29. The system of claim 23 wherein the distal end of the container is selectively matable with a drug housing mounted in fluid tight communication over the target material.

30. The system of claim 24 wherein the biologic material is a patient's skin.

31. A shock wave generating system, comprising: a container having proximal and distal ends; at least one pair of electrodes disposed within said container; and a membrane coupled to the distal end of the container and having a first surface that receives a shock wave generated upon an electric current passing between said at least one pair of electrodes, and a second, opposed surface that transmits the shock wave received by the first surface to a target material.

32. The system of claim 31 wherein the target material is a biologic material.

33. The system of claim 31 wherein the target material is a medicament in contact with a biologic material.

34. The system of claim 31 wherein the distal end of the container is selectively matable with a drug delivery housing mounted in fluid tight communication with the target material.

35. The system of claim 34 further comprising a sealing element effective to create the fluid tight communication between the target material and the drug housing.

36. The system of claim 31 wherein said container comprises a shock generating chamber at said proximal end of said container and a shock tube coupled to and extending from said shock generating container to terminate at said distal end of said container.

37. The system of claim 36 wherein the at least one pair of electrodes is disposed along an axis substantially orthogonal to the length of the shock tube.

38. The system of claim 31 further comprising a second pair of electrodes, wherein a first current is passed between a first electrode of the first pair of electrodes and a first electrode of the second pair of electrodes and a second current is passed between a second electrode of the first pair of electrodes and a second electrode of the second pair of electrodes.

39. The system of claim 31 wherein the shock generating chamber is gas impermeable and able to receive pressurized gas.

40. The system of claim 31 wherein the shock generating chamber is liquid impermeable and able to receive pressurized liquid.

41. A drug delivery system, comprising: a container; at least one pair of electrodes disposed within said container and adapted for passing a current therebetween to generate a shock wave; and a membrane having a first surface that receives the shock wave and a second, opposed surface that transmits the shock wave received by the first surface to a target material.

42. The system of claim 41 wherein the target material is a biologic material.

43. The system of claim 41 wherein the target material is a medicament in contact with a biologic material.

44. The system of claim 41 wherein the membrane is mounted to a distal end of the container so as to cover an opening at the distal end.

45. The system of claim 41 wherein the membrane is provided by a drug housing mounted in fluid tight communication with the target material.

46. The system of claim 41 further comprising a sealing element effective to create a fluid tight communication between the target material and a drug housing, wherein the membrane is mounted to the sealing element.

47. A method of administering a drug, comprising the steps of: providing a drug to a biologic material; providing a container having at least a pair of electrodes therein; and passing an electric current between said at least one pair of electrodes so as to cause a shock wave to be transmitted through an opening in the container to the biologic material.

48. The method of claim 47 wherein the biologic material comprises living tissue.

49. The method of claim 47 wherein the container providing step includes providing the container with a shock generating chamber and a shock tube coupled to and extending from the shock generating chamber to terminate at the opening at a distal end of the container.

50. The method of claim 49 further comprising the step of providing a membrane adjacent to the distal end of the container through which the shock wave is transmitted to the biologic material.

51. The method of claim 49 wherein the container providing step includes providing the at least one pair of electrodes along an axis substantially orthogonal to an elongated axis of the shock tube.

52. The method of claim 47 wherein the container providing step includes providing at least two pairs of electrodes within the container.

53. The method of claim 52 wherein the current passing step comprises the steps of: passing a first current between a first electrode of the first pair of electrodes and a first electrode of a second pair of electrodes; and passing a second current between a second electrode of the first pair of electrodes and a second electrode of the second pair of electrodes.

54. The method of claim 47 wherein the drug providing step includes topically applying the drug to the biologic material.

55. The method of claim 47 wherein the drug providing step includes injecting the drug into a patient to which the drug is being administered.

56. The method of claim 55 wherein the drug is injected in a manner selected from the group consisting of intravenously, intradermally and intramuscularly.

57. The method of claim 47 wherein the drug providing step includes applying a transdermal patch to the biologic material.

58. The method of claim 49 wherein the shock wave is transmitted to the biologic material after said transdermal patch is applied to the biologic material.

59. The method of claim 49 wherein the shock wave is transmitted to the biologic material before said transdermal patch is applied to the biologic material.

60. A shock wave generating system, comprising: a container comprising: a shock generating chamber; a shock tube coupled to the shock generating chamber and extending therefrom to terminate at a distal end through which a shock wave is transmitted to a target material adapted for receiving a medicament; and a shock wave generating mechanism disposed within said shock generating chamber; and a transport enhancement mechanism for enhancing absorption of the medicament by the target material.

61. The shock wave generating system of claim 60 wherein said shock wave generating mechanism is an electric discharge mechanism.

62. The shock wave generating system of claim 60 wherein said shock wave generating mechanism is a rapidly openable divider.

63. The shock wave generating system of claim 60 wherein the shock wave generating mechanism is a piston.

64. The shock wave generating system of claim 60 further comprising a membrane coupled to the distal end of the shock tube for receiving a shock wave traveling through said shock tube and transferring said shock wave to said target material.

65. The shock wave generating system of claim 60 wherein said transport enhancement mechanism is an ultrasound unit.

66. The shock wave generating system of claim 60 wherein said transport enhancement mechanism utilizes iontophoresis.

67. The shock wave generating system of claim 60 wherein said transport enhancement mechanism is a surfactant.

68. The shock wave generating system of claim 60 wherein said transport enhancement mechanism provides a mechanical vibration.

69. The shock wave generating system of claim 60 wherein said transport enhancement mechanism provides a high pressure gradient to the target material.

70. The shock wave generating system of claim 60 wherein said transport enhancement mechanism is coupled to said container.

71. The shock wave generating system of claim 60 wherein said transport enhancement mechanism is separate from said container.

72. The shock wave generating system of claim 60 wherein said transport enhancement mechanism is actuated to enhance absorption of the medicament by the target material simultaneously with a shock wave being generated by said shock wave generating mechanism.

73. The shock wave generating system of claim 60 wherein said transport enhancement mechanism is actuated to enhance absorption of the medicament by the target material after a shock wave is generated by said shock wave generating system.

74. The shock wave generating system of claim 60 wherein said transport enhancement mechanism is a laser and the medicament is a compound that absorbs laser energy at a predetermined wavelength corresponding to a wavelength emitted by the laser.

75. A method of administering a drug comprising the steps of: providing a drug to a biologic material; applying a shock wave to said biologic material with a shock wave initiator in order to increase the porosity of the biologic material and absorption of the drug, the shock wave initiator comprising a shock generating chamber and a shock tube coupled to the shock generating chamber and having a membrane mounted to a distal end through which said shock wave is transmitted to the biologic material; and further increasing the absorption of the drug by the biologic material.

76. The method of claim 75 wherein the biologic material comprises living tissue.

77. The method of claim 75 wherein the shock wave applying step comprises the step of passing a current between at least one pair of electrodes disposed in said shock generating chamber.

78. The method of claim 75 wherein said shock wave applying step comprises the step of actuating a piston disposed in said shock generating chamber.

79. The method of claim 75 wherein said shock wave applying step comprises the step of opening a rapidly openable divider disposed in said shock generating chamber.

80. The method of claim 75 wherein said step of further increasing the absorption comprises the step of applying ultrasound energy to the biologic material.

81. The method of claim 75 wherein said step of further increasing the absorption comprises the step of utilizing iontophoresis.

82. The method of claim 75 wherein said step of further increasing the absorption comprises the step of applying a surfactant to the biologic material.

83. The method of claim 75 wherein said step of further increasing the absorption comprises the step of applying a mechanical vibration to the biologic material.

84. The method of claim 75 wherein said step of further increasing the absorption comprises the step of applying a high pressure gradient to the target material.