AU2006252145A1 - Synergetic drug delivery device - Google Patents
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- AU2006252145A1 AU2006252145A1 AU2006252145A AU2006252145A AU2006252145A1 AU 2006252145 A1 AU2006252145 A1 AU 2006252145A1 AU 2006252145 A AU2006252145 A AU 2006252145A AU 2006252145 A AU2006252145 A AU 2006252145A AU 2006252145 A1 AU2006252145 A1 AU 2006252145A1
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Regulation 3.2
AUSTRALIA
Patents Act 1990 (Cth) SHEIMAN ULTRASONIC RESEARCH FOUNDATION PTY LTD COMPLETE SPECIFICATION FOR A DIVISIONAL APPLICATION Invention Title: SYNERGETIC DRUG DELIVERY DEVICE The following statement is a full description of this invention, including the best method of performing it known to us: Regulation 8.2 (3) 201727301.1 201284710_1
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2 0 O Synergetic drug delivery device SField of the Invention 00 The present invention relates broadly to transdermal drug delivery and therapy devices. The invention also relates generally to a method or device for delivering a substance to a cellular organism. The invention relates particularly, though not exclusively, to nebulization of drugs and radiation or energy assisted delivery of aerosol C and non aerosol forms of drugs to cellular organisms.
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SBackground to the Invention Transdermal drug delivery systems are known and there are two methods by which drugs can be delivered through the skin: passive diffusion and active transport.
Passive diffusion involves placing a concentration of a drug over the surface of the skin and allowing the drug to diffuse through the skin. Due to the natural skin barriers, few pharmaceuticals with sufficiently small molecular size have been successfully passively diffused into the body. A more viable way for drugs to penetrate the skin's barriers is by means of an active energy source that pushes drug molecules through the skin. That allows a greater quantity of medicine and medicine of a greater molecular size to be delivered in a shorter time frame. There are several types of active transdermal drug delivery systems: iontophoresis, electroporation, phono/sonophoresis, magnetophoresis and electromagnetophoresis.
The application of electrical fields to create transient transport is known as electroporation. The method to electrically transport charged drug molecules through the skin is known as iontophoresis. Electroporation creates transient pores in the lipid bilayers of the stratum comeum, the outermost layer of skin. Iontophoresis provides an electrical driving force to move charged compounds. Electroporation involves application of electric field pulses that create transient aqueous pathways in lipid bilayer membranes, causing a temporary alteration of skin structure. While occurrence of aqueous pores may allow transdermal permeation of neutral molecules by diffusion, the transport of charged molecules during pulsing occurs predominantly by electrophoresis and electroosmosis.
201284710_1 O 3 Iontophoresis has been used to increase the permeability of skin to drugs, and 0 involves the application of an external electric field, and topical delivery of an ionized form Sof drug (or of a neutral drug carried with the water flux associated with ion transport, i.e., 00 via "electroosmosis"). While permeation enhancement via iontophoresis has, as with chemical enhancers, been effective, there are problems with the degree of irreversible skin n damage induced by the transmembrane passage of current. Ionophoresis tends to work only if the molecules can be dissociated into positive and negative ions and then driven in.
A primary disadvantage of this technique is that many drugs cannot be dissociated.
IND Another disadvantage is that many drugs lose their effectiveness if broken up in this 0 C 10 manner. Electroporation and iontophoresis have both been proven ineffective to deliver therapeutically adequate dosages of many medications through the skin.
The effects of sonophoresis on skin result from the release of energy. These include the non-thermal effects of cavitation, and mechanical stress as well as thermal effects. It appears that ultrasound exposure in the therapeutic range causes cavitation in the keratinocytes of the stratum corneum as the primary effect in increasing skin permeability for transcutaneous transport of topical agents. Sonophoresis has been shown to enhance transdermal transport of various drugs. Although a variety of ultrasound conditions have been used for sonophoresis, the most commonly used conditions correspond to the therapeutic ultrasound (frequency in the range of 1 MHz-3 MHz, and intensity in the range of 0-2 W/cm).
In spite of these advantages, very few drugs are currently administered transdermally for clinical applications because of the low skin permeability to drugs.
Application of therapeutic ultrasound does not induce transdermal transport of highmolecular weight proteins. It is a common observation that the typical enhancement induced by therapeutic ultrasound is less than ten-fold. This low permeability is attributed to the stratum corneum Application of low-frequency (20 kHz) ultrasound dramatically enhances transdermal transport of drugs. Transdermal transport enhancement induced by low-frequency ultrasound was found to be as much as 1000-fold higher than that induced by high-frequency ultrasound.
Application of low-frequency ultrasound appears to induce cavitation inside as well as outside the skin. Cavitation occurring at either location may cause disordering of the SC lipids. In addition, oscillations of cavitation bubbles may result in significant water 201284710_1 IND 4 penetration into the disordered lipid regions. At the same time, use of low-frequency U ultrasound of high intensity for inducing cavitation represents a serious problem for the Shealth of the patient. Excepting a destructive action on the surface of the skin, the low- 0_ frequency ultrasound (due to the small attenuation) is capable of deeply penetrating into an organism, rendering serious damage. There is data on serious diseases of researchers, n chronically exposed to low-frequency ultrasound, including by disinfection of the hands in an ultrasonic bath. The research of the safety of low frequency ultrasound showed that Sonly low intensities could be safe.
US patent 5741317 discloses an apparatus which includes a therapy and drug C1 10 treatment tub for submersion of a treatment area of a patient in a medicated solution. The tub includes acoustic transducers and rows of electrodes and coils for delivery of respective ultrasonic, electric and magnetic radiation to the patient. The radiation facilitates active transdermal drug delivery involving phonophoretic, iontophoretic and electromagnetophoretic transport mechanisms. However, the apparatus is very large and expensive and cannot readily be used for transdermal drug delivery to a specific region of a patient.
US patent 5983134 discloses a flexible cuff connected to a liquid drug reservoir. The cuff is designed for attachment to a patient by wrapping around part of the patient's body to form an attached sleeve. Referring to figure 1 of US 5983134, the attached sleeve can be elongate and encircle most of a patient's leg, or squat and encircles a patient's neck. The cuff is designed to transmit electric and magnetic fields to assist transdermal delivery of drugs provided at an internal cylindrical surface of the attached sleeve. While the cuff of US 5983134 is suitable for transdermal drug delivery to a specific part of a patient's body, it is cumbersome to use and is only suitable for delivery of a drug to a circumferential segment of a patient's limb, torso or neck.
US patent 5464386 discloses a transdermal drug delivery applicator which is designed to supply a fluid medium carrying drug loaded vesicles to a patient's skin via a curved head assembly. The applicator generates a pulsed electrical field to facilitate active transdermal transport mechanisms of electroporation and iontophoresis. The applicator is capable of providing active transdermal drug delivery to a specific part of a patient's body.
However, the applicator is only able to provide active transdermal drug delivery involving electric radiation.
201284710_1 N 0 Summary of the Invention SAccording to one aspect of the present invention there is provided a method of 0 delivering a substance into a cellular organism, the method comprising the steps of: providing the substance in an ionised aerosol form at a delivery region of the organism; and applying magnetic energy to the delivery region to effect enhanced delivery of the \ionised aerosol substance to the cellular organism.
SPreferably the application of magnetic energy is effected by applying a pulsed magnetic field. More preferably the pulsed magnetic field is asymmetric.
According to another aspect of the invention there is provided a method of delivering a substance into a cellular organism, the method comprising the steps of: providing the substance in a liquid or cream form at a delivery region of the organism; applying ultrasonic energy to the delivery region to enhance delivery of the cream or liquid substance to said organism; and simultaneously applying magnetic energy and electrical energy to the delivery region to effect delivery of the cream or liquid substance to the cellular organism.
Preferably the application of ultrasonic energy to said organism to enhance delivery is promoted by opening of pores of the organism.
Preferably the ultrasonic and magnetic energies are applied simultaneously.
Preferably the application of ultrasonic, magnetic and/or electrical energy is effected by applying ultrasonic, magnetic and/or electrical fields, respectively, the magnetic field is a pulsed magnetic field.
According to a further aspect of the invention there is provided a device for delivering a substance into a cellular organism, the device comprising: 201284710_1 N 6 0 an aerosol delivery head for providing the substance in an ionised aerosol form at a O delivery region of the organism; means for applying magnetic energy to the delivery region to effect enhanced 0 delivery of the ionised aerosol substance to the cellular organism.
V) 5 Preferably the aerosol delivery head is configured to defines a compartment about the delivery region.
SPreferably the device also comprises a nebulizer being operatively coupled to the 8 aerosol delivery head. More preferably the nebulizer includes: a container being adapted to contain a liquid to be nebulized; and an energy source being operatively coupled to the container for nebulization of the liquid and being arranged for transmission of energy to the liquid which is nebulized in the form of the aerosol.
Preferably the nebulizer also includes an aerosol tube having a cross-sectional area such that the positive pressure of the aerosol within the aerosol tube induces a pressure drop along the aerosol tube which alone is sufficient to propel the nebulised aerosol through the aerosol tube.
According to yet another aspect of the invention there is provided a device for delivering a substance into a cellular organism, the device comprising: means for generating ultrasonic energy being adapted to cooperate with a delivery region of the organism to enhance delivery of the substance in a cream or liquid form to said organism; means for simultaneously applying magnetic energy and electrical energy to the delivery region to effect delivery of the cream or liquid substance to the cellular organism, said ultrasonic generating means being operatively coupled to the magnetic and electrical energy means whereby a synergistic effect is provided by the combination of said means.
Preferably the means for applying magnetic energy is in the form of a pulsed magnetic generator.
2012847101 \ID 7 O The organism of the various aspects of the present invention may be an animal.
O More particularly, the organism may be a human being. The delivery region may comprise Sa membrane of the animal or human being. The membrane may comprise skin or tissue of 00 the human being. Alternatively, the membrane may comprise a cornea of the human being. The membrane may alternatively comprise a lung of the human being.
Brief Description of the Drawings t' A preferred embodiment of the present invention will now be described, by way of \ID example only, with reference to the accompanying drawings, in which: SFigure 1 is a schematic side elevational view of a magnetic radiation transderinal aerosol delivery gun; Figure 2 is a schematic side elevational view of one example of internal components of a substance delivery gun similar to the aerosol delivery gun of figure 1; Figure 3 is a fluorescence confocal image of a stratum corneum skin layer showing active transdermal delivery of a fluorescent dye to this layer of a subject using the substance delivery gun of figure 2; Figure 4 is an image corresponding to that of figure 3 of a deeper skin layer, the stratum spinosum; Figure 5 is an image corresponding to that of figure 3 showing slightly deeper penetration of the fluorescent dye; Figure 6 is a schematic side elevational view similar to that of figure 2 showing another example of a substance delivery gun; and Figure 7 is a schematic side elevational view similar to that of figure 2 showing a third example of a substance delivery gun.
Detailed Description of the Preferred Embodiment In the various embodiments of the method and device for delivering a substance to a cellular organism, different combinations of the sources of energy are utilized for a synergetic effect on for example drug delivery. To achieve improved efficiency the drug 2012847101
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I8 O delivery probe is constructed such that the energy fields interact to enhance drug delivery.
O For example, the device components may be concentrated in the same region of space. In Sthis case the maximum combined energy of the drug delivery system will be concentrated 00 into the delivery area and the synergetic effect is achieved. Another approach to enhance the efficiency of active molecules delivery is to increase the surface energy/area of the n substance to be delivered. This may be achieved, for example, by nebulisation. The following embodiments provide several examples of the synergetic devices for drug t delivery. The improved or optimal efficiency of the device is achieved when all the sources O of energy are coaxial, or generally aligned. This improvement from the synergistic effect of the "focussed" or concentrated energy fields of the drug delivery device is akin to the provision of coherent light from a laser source.
As shown in figure 1, aerosol produced by an ultrasonic nebulizer is administered to a delivery region of a cellular organism in the form of a patient treatment site 112. This is effected by the use of a substance delivery device which in this example is also a handheld device in the form of an aerosol delivery gun 110. The aerosol gun 110 has particular application in the field of wound management.
In this example, the patient treatment site 112 is a specific region of the skin of a patient, which requires administration of an aerosol form of a drug. However, the patient treatment site could be for example a patient's cornea. The patient treatment site can also include an opening to a patient's lungs involving their mouth and/or nose or more specifically a membrane of the patient's lungs. The aerosol delivery gun 110 includes radiation or energy generating means for enhancing delivery of aerosol 103 to the patient treatment site 112. In this particular example the radiation or energy generating means is a magnetic field generator which includes a magnetic inductor 116 and a corresponding electronic generator 118. The aerosol delivery gun 110 also includes an aerosol delivery head which in this example comprises aerosol delivery compartment 114 for provision of aerosol 103 to the patient treatment site 112.
The aerosol delivery compartment 114 includes walls 120 which extend away from the magnetic inductor 116 in a divergent manner. A compartment outlet in the form of aerosol outlet 125 is formed in the delivery compartment walls 120 which are designed for application against the patient treatment site 112 to create a compartment. If the patient treatment site is a patient's cornea, the aerosol delivery compartment is designed so that 2012847101 I9
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O the walls 120 contact skin covering the patient's eye socket to form a compartment covering the cornea. The compartment enables aerosol 103 to be contained between the patient Streatment site 1*12 and the magnetic inductor 116, and evenly dispersed over the patient 00 treatment site 112. The compartment 114 is designed to allow the aerosol 103 to flow through it, for example by venting at a predetermined pressure. The aerosol 103 can be n supplied to the aerosol compartment 114 using an ultrasonic nebulizer 126. The aerosol may also be recirculated through the compartment 114. In this instance the general configuration of the aerosol chamber or compartment 114 and the aerosol generator or IND nebulizer 126 is similar to that disclosed in the applicants granted US patent no. 6,379,616.
The nebulizer 126 may be similar in construction to those described in the parent application no. 2003254386 from which this application was derived. The contents of this parent application are to be considered included herein by way of reference.
With aerosol 103 contained within the aerosol delivery compartment 114 as shown in figure 1 passive transdermal aerosol delivery to the patient via the patient treatment site 112 is more effective than it would be if the aerosol was otherwise delivered. The aerosol delivery compartment 114 of the aerosol delivery gun 110 therefore promotes dispersion and broad coverage of the aerosol 103 near the patient treatment site 112. The aerosol delivery gun 110 further enhances transdermal delivery of aerosol 103 which condenses on the patient treatment site 112 by applying a magnetic field, via the magnetic inductor 116, to the patient treatment site 112. The general direction of propagation of the magnetic field is represented by arrow 128. The magnetic field facilitates the active transdermal transport technique known as magnetophoresis.
The aerosol delivery gun 110 is effective for delivery of a substance to sensitive patient treatment areas, for example, a patient's cornea. It enables the substance to be applied to the cornea without the cornea being contacted by anything other than the aerosol 103. This is possible because the magnetic field generator of the aerosol delivery gun 110 does not contact the patient treatment site. The aerosol delivery gun 110 is also effective for delivery of a substance to a patient's lungs.
By ionising the aerosol 103 it can be more efficiently and effectively delivered to the patient treatment site 112. The ionised aerosol 103 is attracted to the patient treatment site 112 by oppositely charging the patient treatment site 112. The aerosol 103 can be charged before or after its entry into the aerosol delivery compartment 114.
201284710_1 O The handheld device 110 of Figure 1 is in the form of an aerosol delivery gun which O uses the synergy of two sources of energy applied to the treatment site 112. The first Ssource of energy is the ultrasonic nebulizer 126 which converts the liquid phase of the 00 delivering substance, in an aerosol form 103. As a result the surface area and respectively the surface energy of the substance will dramatically increase. The aerosol delivery gun I 110 includes radiation energy means for enhancing delivery of aerosol 103 to the patient treatment site 112.
-i In this particular example the second source of energy is a magnetic field generator, which includes the magnetic inductor 116, and the corresponding electronic generator 118.
i 10 Efficiency of the aerosol delivery is enhanced by the magnetic field preferably pulse magnetic fields. This magnetic field passes through the aerosol chamber 114 to the surface 112 to be delivered. With the aerosol 103 contained within the aerosol delivery compartment 114 passive transdermal aerosol delivery to the patient via the patient treatment site 112 is more effective than it would be if the aerosol 103 was otherwise delivered. The aerosol delivery compartment 114 of the aerosol delivery gun 110 promotes broad coverage of the aerosol 103 near the patient treatment site 112. The aerosol delivery gun 110 further enhances transdermal delivery of aerosol 103, which condenses on the patient treatment site 112 by applying a magnetic field, via the magnetic inductor 116, to the patient treatment site 112. The general direction of propagation of the magnetic field is represented by arrow 128. The magnetic field facilitates the active transdermal transport technique known as magnetophoresis.
It is recognised that the difference between the dielectric permittivity of free space and living tissue is quite large, owing to the high concentration of mobile charge carriers and dipoles in the latter. In contrast, the magnetic permittivity of tissue compared to free space is not great, as tissue does not have a large concentration of magnetic dipoles.
Consequently, external magnetic fields propagate into tissue, whereas external electric fields do not do so effectively. For instance, a weak 60 Hz 0.53mT magnetic field induces a current density of about 1 mA/m 2 over a 10 cm region. To produce the same current with an external electric field would require about 250 kV/m. This embodiment of the invention effectively uses short magnetic field pulses to induce the effects of pulsed electric fields including electroporation, and AC electroosmotic effects.
2012847101 S11 O It is also recognised that magnetic fields propagate through space and through O tissue. To achieve effects within tissue, it is not necessary to physically contact the tissue, Sas with a DC electric field probe. This is of particular interest for sensitive or traumatized 00 tissue such as bums or wounds, eye etc. Transdermal delivery can according to this embodiment of the invention be enhanced without physical contact to the skin.
Figure 2 schematically depicts another example of a handheld device in the form of a substance delivery gun 132 which is suitable for delivering a substance, for example, in aerosol, liquid or gel form, to a delivery region of a cellular organism which in this example is patient treatment site 134. The patient treatment site 134 is analogous to the S 10 patient treatment site 112 described above in relation to the aerosol delivery gun 110. The substance delivery gun 132 houses radiation or energy generating means for generation of three different forms of radiation or energy which in this example include sonic or ultrasonic, electric and magnetic radiation. The substance delivery gun 132 also includes a radiation delivery head which can take the form of a radiation delivery plate 145. The substance delivery plate 145 can be used for delivery of, for example, a liquid or gel form of a substance to the patient treatment site 134. However, when the substance delivery plate 145 is used for aerosol delivery, the corresponding radiation or energy generating means generating sonic or low frequency ultrasonic radiation either alone or in combination with electric and/or magnetic radiation. High frequency ultrasonic radiation is not used for aerosol delivery because it requires a liquid or gel medium for effective transmission.
By providing a substance at the patient treatment site 134, via the substance delivery compartment or substance delivery plate 145 the substance delivery gun 132 aids passive transdermal drug delivery for reasons described above in relation to the aerosol delivery gun 110. The substance delivery gun 132 further enhances transdermal substance delivery by simultaneously applying ultrasonic, electric and magnetic fields to the patient treatment site 134 which, in the case of substance delivery compartment, aerosol 103 is contained at the patient treatment site 134, and in the case of the substance delivery plate 145, a gel form of a substance is located at the patient treatment site 134. The ultrasonic, electric and magnetic radiation applies to the substance respective active transdermal transport techniques of sonophoresis, iontophoresis and electroporation, and magnetophoresis.
201284710_1 ND 12 O Referring to figure 2, the substance delivery gun 132 includes an ultrasonic field O generator which in this example consists of an electro acoustic transducer 136 and an Selectronic generator 144. The electronic generator 144 supplies power to the electro 00 acoustic transducer 136. The electro acoustic transducer is formed of a piezoceramic 138 which is covered on opposite sides by metal electrodes 140 and 142. The electro acoustic I transducer 136 is formed of diamagnetic material which is transparent to magnetic fields generated by the magnetic field generator.
The electric field generator of the substance delivery gun 132 is in the form of a direct current electric circuit 146 which connects the patient treatment site 134 to the metal C 10 electrode 142 via electrode 143. The direct current electric circuit 146 includes an electric current generator 148. The magnetic field generator of the substance delivery gun 132 is in this particular example a magnetic inductor 150 which is supplied electric current by an electronic generator 152. The electronic generator 152 is designed to produce different forms of voltage to create different types of magnetic fields including asymmetric pulse magnetic fields.
The general direction of propagation of the ultrasonic, electric and magnetic fields is represented by arrow 160. The radiation field generators of the substance delivery gun 132 are designed to simultaneously generate each of the three different forms of radiation fields. The fields are one example of how ultrasonic, electric and magnetic fields can be combined in a synergistic manner whereby the three different forms of radiation fields collectively enhance delivery more than the sum of delivery enhancements achievable through independent application of the three different forms of radiation fields.
Fluorescence confocal images 210, 212 and 214 of the figures 3, 4 and 5 respectively demonstrate the effectiveness of the substance delivery gun 132. The fluorescence confocal images 210, 212 and 214 are images of three different layers of a subject's skin following transdermal delivery of a fluorescent dye through the skin using the substance delivery gun 132. The fluorescent dye was delivered to the subject over a six minute period of time using the substance delivery gun 132 having radiation or energy generating means for simultaneous generation of ultrasonic, electric and magnetic radiation fields defined by the following respective parameters: 0.88 MHz at 1W/cm 2 intensity and a 50% duty cycle of lmA; and 2012847101 IND 13 0 SImage 210 is an image of a stratum comeum layer, image 212 is an image of a O deeper stratum spinosum layer and image 214 is an image of a third layer which is slightly Sdeeper than that corresponding to image 212. Bright regions of images 210, 212 and 214 00 represented by reference numerals 216, 218 and 220 respectively indicate the presence of fluorescent dye.
Referring to figure 3, the bright regions 216 correspond to intercellular space N between corneocyte cells of the stratum corneum. The bright regions 216 therefore indicate Sthe presence of fluorescent dye in the intercellular spaces of the stratum corneum.
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SThe stratum spinosum skin layer of image 212 is formed mainly of keratinocyte cells with the remainder of this layer being formed of a fibrous arrangement of cells known as the dermal papillae which protrude into the stratum spinosum layer from a slightly deeper region of the skin. The bright coloured regions 222 are unclear in the image 212 however in the corresponding original image bright coloured regions 222 form a honeycomb structure. Bright regions 222 indicate the presence of fluorescent dye in intercellular space between keratinocyte cells. Bright region 224 is also unclear although the corresponding original image gives the appearance of a dark annular region having light distributed throughout. Bright regions 224 indicate the presence of fluorescent dye throughout the dermal papillae.
Image 214 of figure 5 corresponds to a skin layer formed predominantly of dermal papillae. Visible in image 214 is a fluorescent dye stained dermal papillae 226 and the edge of another fluorescent dye stained dermal papillae 228.
Transdermal delivery of a fluorescent dye using a substance delivery gun 132 resulted in the delivery of fluorescent dye to each of the layers represented by the images of figures 3, 4 and 5. Passive delivery of a fluorescent dye to the subject results in a similar concentration of dye to that represented by image 210 reaching the stratum corneum layer over a six minute time period. However, regardless of the elapsed time, fluorescent dye does not reach skin layers corresponding to images 212 or 214 via passive diffusion techniques.
A substance delivery gun 170 which is schematically represented by figure 6 is a modified version of the substance delivery gun 132. For ease of reference like features of the substance delivery guns 132 and 170 are referred to by common reference numerals.
201284710_1 INO 14 0 O The substance delivery gun 170 includes an energy concentrator 172. An electro acoustic O transducer 174 is positioned at an end of the energy concentrator 172 which is remote from Sa patient treatment site 178. A direct current electric circuit 180 connects the patient 00 treatment site 178 to the energy concentrator 172. The direct current electric circuit 180 includes an electric current generator 148 referred to above in relation to the substance I delivery gun 132. In place of the magnetic inductor 150 of the substance delivery gun 132, the substance delivery gun 170 includes a magnetic inductor 182 which is mounted to a trn tapered end 184 of the energy concentrator 172 which is adjacent the patient treatment site INO 178. The magnetic inductor 182 is connected to an electronic generator 152 referred to in relation to the substance delivery gun 132. The energy concentrator 172 is constructed from a metal having ferromagnetic properties which enable magnetic and acoustic fields of the substance delivery gun 170 to be enhanced. The concentrator 172 may also be fabricated from materials having non-ferromagnetic properties. The concentrator 172 may include a co-axial opening (not shown) which provides a delivery passageway for the substance. This can also apply to the other embodiments.
The substance delivery gun 170 otherwise corresponds to the substance delivery gun 132 and includes features described above in relation to the substance delivery gun 132. The substance delivery gun 170 however has, by virtue of the energy concentrator 172 enhanced substance delivery capability to that of the substance delivery gun 132.
Referring to figure 7, another alternative form of the substance delivery gun 132 of figure 2 is substance delivery gun 186. Details of the substance delivery gun 186 are explained by reference to substance delivery guns 132 and 170 of figures 1 and 2 respectively. Like features of substance delivery guns 132, 170 and 186 are referred to by common reference numerals. The substance delivery gun 186 includes an electro acoustic transducer 188 consisting of a piezoceramic 190 and metal electrodes 192 and 194 which sandwich the piezoceramic 190 there between, a magnetic inductor 182 and a corresponding electronic generator 152 referred to above in relation to the substance delivery gun 132, and a direct current electric circuit. The electro acoustic transducer 188 is similar to the electro acoustic transducer 136 except that it includes apertures 196 for passage there through of electroporation electrodes 198. The direct current electric circuit 180 is identical to the direct current electric circuit 180 of the substance delivery gun 170 except that an outlet of the electric current generator 148 connects with the metal electrode
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201284710_1 \O 0 O 194. The magnetic radiation generating means of the substance delivery gun 186 includes a magnetic inductor 182 which is as described above in relation to the magnetic inductor 182 Sof the substance delivery gun 170 except that it encircles electroporation electrodes 198 00 rather than a tapered end of an energy concentrator.
The electrodes 198 form part of a second electric generator which in this example enables electroporation to be applied to a substance for its delivery to a patient treatment C site 200. The second electric generator, in this particular example, also includes an electric C, generator 202 which generates electricity for the electroporation electrodes 198. The electroporation electrodes 198 can be made of a ferromagnetic material which helps to Cr 10 concentrate and transport magnetic radiation to the patient treatment site. During delivery of the substance to the patient treatment site 200, the substance functions as a transmission medium for ultrasonic energy emitted by the electro acoustic transducer 188.
These embodiments also provide an application for non contact transdermal drug delivery and enhancement. In these examples, a magnetic field can enhance transdermal contact with distressed or sensitive tissue. Traditionally, drug application to such tissue requires physically contact. However, in these embodiments the production of high density aerosols of drug materials in combination with a remote magnetic inductor allows both material delivery and transport enhancement without direct contact to the target tissue. Further, a particular combination of nebulized drug with a pulsed magnetic field provides a non-contact mode of drug delivery with enhanced transport. This is of particular interest for treatment of sensitive or traumatized tissue, such as the eye, or for bums. A pulsed magnetic field induces an electric field pulse. If the induced electric field is of sufficient strength, the electric field can effect electroporation as well as transient electroosmotic flow. A magnetic field pulse thus gives access to the effects of an electric field pulse, with certain advantages.
The individual effects described above provide improved transport for particular types of molecules. In combination, the permeability of the stratum comeum and other cellular organisms to all drug types is enhanced by a simultaneous increase in lipophilic permeability, hydrophilic permeability, and active transport strategies including iontophoresis, electroosmotic transport and hydrodynamic effects. Poration can be effected by transient electroporation, sonoporation or magnetoporation. Any of these methods produces a pathway for hydrophilic drugs that lasts for a window of many minutes. A 201284710_1 16 weak electric field in this window period can induce iontophoretic or electrosmotic transport. Pulsed magnetic fields can also enhance these transport modes. A pulsed magnetic field can also induce electrosmotic transport.
Ultrasound enhances transport by increasing the mobility of the lipid bilayer. This is significant on its own for lipophilic molecules, but in combination with poration allows transport of surface active molecules such as steroids which would otherwise be topologically trapped, and confined to a single hydrophilic domain. Additionally, the field intensities required to effect each mode of permeability enhancement are lowered. A membrane carrying a modestly enhanced charge density (perhaps induced by an applied electric field) is more susceptible to poration by ultrasound. An ultrasonically stressed and fluidized membrane is more susceptible to poration by a magnetic field pulse. Overall, the required levels of individual field intensities are reduced. The potential for damaging effects on tissue, such as from sustained high transdermal electric currents or sustained cavitation, especially at low frequencies which penetrate into deep tissue, are reduced.
Therefore, these embodiments of the invention provide both safe and effective transport mechanisms.
Now that various examples of a preferred embodiment and method of delivering a substance into a cellular organism have been described, it will be apparent to those skilled in the art that the preferred embodiment and methodology have at least the following advantages: the device effectively provides an aerosol form of a substance at a delivery region of a cellular organism for delivery thereto; the application of an aerosol form of a substance to delivery regions of a cellular organism is possible where contact of the delivery regions by liquid or solid matter is adverse or sensitive; the delivery of an aerosol form of a substance into a cellular organism is possible through active transport techniques involving the application of one or more forms of radiation or energy; the delivery of an aerosol form of a substance into a cellular organism is possible through simultaneous application of two or more different forms of radiation or energy; the delivery of an aerosol form of a substance into a cellular organism is possible through simultaneous application of two or more different forms of 201284710_1 ID17 O radiation or energy in a synergistic manner whereby different form of Uradiation or energy collectively enhance delivery more than the sum of Sdelivery enhancements achievable through independent application of the 00 different forms of radiation or energy; the substance delivery can be confined to a relatively small part of a cellular Sorganism by simultaneous application of two or more different forms of radiation via a radiation delivery head of a substance delivery gun; and S(g) the delivery of a substance via a delivery gun through simultaneous IN application of two or more different forms of radiation or energy in a synergistic manner whereby different forms of radiation or energy collectively enhance delivery more than the sum of delivery enhancements achievable through independent application of the different forms of radiation or energy.
Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. All such variations and modifications are to be considered within the scope of the present invention the nature of which is to be determined from the foregoing description.
It is to be understood that a reference herein to a prior art document does not constitute an admission that the document forms part of the common general knowledge in the art in Australia or in any other country.
Claims (17)
1. A method of delivering a substance into a cellular organism, the method 00 comprising the steps of: providing the substance in an ionised aerosol form at a delivery region of the organism; and applying magnetic energy to the delivery region to effect enhanced delivery C1 of the ionised aerosol substance to the cellular organism. IN
2. A method as defined in claim I wherein the application of magnetic energy is Seffected by applying a pulsed magnetic field.
3. A method as defined in claim 2 wherein the pulsed magnetic field is asymmetric.
4. A method of delivering a substance into a cellular organism, the method comprising the steps of: providing the substance in a liquid or cream form at a delivery region of the organism; applying ultrasonic energy to the delivery region to enhance delivery of the cream or liquid substance to said organism; and simultaneously applying magnetic energy and electrical energy to the delivery region to effect delivery of the cream or liquid substance to the cellular organism.
5. A method as defined in claim 4 wherein the application of ultrasonic energy to said organism to enhance delivery is promoted by opening of pores of the organism.
6. A method as defined in any one of the preceding claims wherein the ultrasonic and magnetic energies are applied simultaneously.
7. A method as defined in any one of the preceding claims wherein the application of ultrasonic, magnetic and/or electrical energy is effected by applying ultrasonic, magnetic and/or electrical fields, respectively.
8. A method as defined in claim 7 wherein the magnetic field is a pulsed magnetic field. 201284710_1 ID18
9. A device for delivering a substance into a cellular organism, the device comprising: an aerosol delivery head for providing the substance in an ionised aerosol Sform at a delivery region of the organism; 00 means for applying magnetic energy to the delivery region to effect enhanced delivery of the ionised aerosol substance to the cellular organism. A device as defined in claim 9 wherein the aerosol delivery head provides a compartment about the delivery region.
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11. A device as defined in either of claims 9 or 10 also comprising a nebulizer being Soperatively coupled to the aerosol delivery head.
12. A device as defined in claim 11 wherein the nebulizer includes: a container being adapted to contain a liquid to be nebulized; and an energy source being operatively coupled to the container for nebulization of the liquid and being arranged for transmission of energy to the liquid which is nebulized in the form of the aerosol.
13. A device as defined in claim 12 wherein the nebulizer also includes an aerosol tube having a cross-sectional area such that the positive pressure of the aerosol within the aerosol tube induces a pressure drop along the aerosol tube which alone is sufficient to propel the nebulised aerosol through the aerosol tube.
14. A device for delivering a substance into a cellular organism, the device comprising: means for generating ultrasonic energy being adapted to cooperate with a delivery region of the organism to enhance delivery of the substance in a cream or liquid form to said organism; means for simultaneously applying magnetic energy and electrical energy to the delivery region to effect delivery of the cream or liquid substance to the cellular organism, said ultrasonic generating means being operatively coupled to the magnetic and electrical energy means whereby a synergistic effect is provided by the combination of said means.
A device as defined in claim 14 wherein the means for applying magnetic energy is in the form of a pulsed magnetic generator. 2012847101 oD 19
16. A method of delivering a substance into a cellular organism, said method being O substantially as herein described with reference to and as illustrated in the Saccompanying drawings. 00
17. A device for delivering a substance into a cellular organism, said device being substantially as herein described with reference to and as illustrated in the accompanying drawings.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2006252145A AU2006252145B2 (en) | 2002-08-23 | 2006-12-18 | Synergetic drug delivery device |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002950965 | 2002-08-23 | ||
| AU2002953039 | 2002-12-02 | ||
| AU2003254386A AU2003254386C1 (en) | 2002-08-23 | 2003-08-25 | Nebulizing and drug delivery device |
| AU2006252145A AU2006252145B2 (en) | 2002-08-23 | 2006-12-18 | Synergetic drug delivery device |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2003254386A Division AU2003254386C1 (en) | 2002-08-23 | 2003-08-25 | Nebulizing and drug delivery device |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2006252145A1 true AU2006252145A1 (en) | 2007-01-18 |
| AU2006252145B2 AU2006252145B2 (en) | 2009-05-07 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2006252145A Ceased AU2006252145B2 (en) | 2002-08-23 | 2006-12-18 | Synergetic drug delivery device |
Country Status (1)
| Country | Link |
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| AU (1) | AU2006252145B2 (en) |
Cited By (3)
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|---|---|---|---|---|
| US9913358B2 (en) | 2005-07-08 | 2018-03-06 | Plasma Surgical Investments Limited | Plasma-generating device, plasma surgical device and use of a plasma surgical device |
| US10463418B2 (en) | 2010-07-22 | 2019-11-05 | Plasma Surgical Investments Limited | Volumetrically oscillating plasma flows |
| US11882643B2 (en) | 2020-08-28 | 2024-01-23 | Plasma Surgical, Inc. | Systems, methods, and devices for generating predominantly radially expanded plasma flow |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7814901B2 (en) | 2005-03-09 | 2010-10-19 | Ric Investments, Llc | Nebulizing drug delivery device with increased flow rate |
| US7721729B2 (en) | 2005-03-09 | 2010-05-25 | Ric Investments, Llc | Nebulizing drug delivery device for ventilator |
| US8056557B2 (en) | 2005-03-09 | 2011-11-15 | Ric Investments, Llc | Nebulizing drug delivery device with barrier |
| US9339836B2 (en) | 2005-05-23 | 2016-05-17 | Biosonic Australia Pty Ltd | Ultrasonic atomization apparatus |
| SE529056C2 (en) | 2005-07-08 | 2007-04-17 | Plasma Surgical Invest Ltd | Plasma generating device, plasma surgical device and use of a plasma surgical device |
| SE529058C2 (en) | 2005-07-08 | 2007-04-17 | Plasma Surgical Invest Ltd | Plasma generating device, plasma surgical device, use of a plasma surgical device and method for forming a plasma |
| US7928338B2 (en) | 2007-02-02 | 2011-04-19 | Plasma Surgical Investments Ltd. | Plasma spraying device and method |
| US8735766B2 (en) | 2007-08-06 | 2014-05-27 | Plasma Surgical Investments Limited | Cathode assembly and method for pulsed plasma generation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2076746C1 (en) * | 1992-06-09 | 1997-04-10 | Педдер Валерий Викторович | Method of injection of medicinal agents into biologic tissue and device for its realization (variants) |
| RU2070062C1 (en) * | 1993-04-20 | 1996-12-10 | Борис Степанович Котов | Ultrasonic inhaler |
| JPH10509632A (en) * | 1995-07-25 | 1998-09-22 | マサチューセッツ インスティチュート オブ テクノロジー | Enhanced transdermal delivery using ultrasound |
| US5947921A (en) * | 1995-12-18 | 1999-09-07 | Massachusetts Institute Of Technology | Chemical and physical enhancers and ultrasound for transdermal drug delivery |
| JP2002500075A (en) * | 1998-01-08 | 2002-01-08 | ソントラ メディカル， インコーポレイテッド | Transdermal transport enhanced by ultrasound transmission |
| RU2177299C2 (en) * | 1999-07-29 | 2001-12-27 | Научно-исследовательский центр курортологии и реабилитации (г.Сочи) Черноморского зонального управления специализированных санаториев | Method for treating cardiac ischemia disease and tension stenocardia of functional class i-ii |
-
2006
- 2006-12-18 AU AU2006252145A patent/AU2006252145B2/en not_active Ceased
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9913358B2 (en) | 2005-07-08 | 2018-03-06 | Plasma Surgical Investments Limited | Plasma-generating device, plasma surgical device and use of a plasma surgical device |
| US10201067B2 (en) | 2005-07-08 | 2019-02-05 | Plasma Surgical Investments Limited | Plasma-generating device, plasma surgical device and use of a plasma surgical device |
| US10463418B2 (en) | 2010-07-22 | 2019-11-05 | Plasma Surgical Investments Limited | Volumetrically oscillating plasma flows |
| US10492845B2 (en) | 2010-07-22 | 2019-12-03 | Plasma Surgical Investments Limited | Volumetrically oscillating plasma flows |
| US10631911B2 (en) | 2010-07-22 | 2020-04-28 | Plasma Surgical Investments Limited | Volumetrically oscillating plasma flows |
| US11882643B2 (en) | 2020-08-28 | 2024-01-23 | Plasma Surgical, Inc. | Systems, methods, and devices for generating predominantly radially expanded plasma flow |
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| AU2006252145B2 (en) | 2009-05-07 |
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