CN1642488A - Substance delivery device - Google Patents

Abstract

A system is adapted to be secured substantially adjacent a body surface of a patient to effect delivery of at least one substance (15) through the body surface and into the patient. The system comprises at least one aperture (9) for receiving at least one ultrasonic transmission. The at least one substance (15) is releasably secured substantially adjacent the at least one aperture (19); an acoustic member (11) is positioned in relation to the at least one aperture (19) to communicate the at least one transmission with the at least one substance (15) to effect delivery of the at least one substance (15) through the patient's body surface.

Description

Material delivery device

technical field

The present invention relates generally to substance delivery systems, and more particularly to ultrasonically enhanced substance delivery devices.

Background technique

Typically, transdermal drug delivery systems use a drug-loaded device or patch that is attached to the patient's skin. The patch allows the pharmaceutical compound contained within the patch to be absorbed through the skin layers and into the patient's bloodstream. Transdermal drug delivery reduces the pain associated with drug injection and intravenous drug administration, as well as the risk of infection associated with these techniques. Transdermal drug delivery also avoids gastrointestinal metabolism of the administered drug, reduces hepatic drug elimination, and provides sustained release of the administered drug. Transdermal drug delivery also improves patient compliance with drug therapy due to the relative ease of drug administration and its sustained release.

Because many pharmaceutical compounds are difficult to absorb through the skin due to the molecular size of the drug or other bioadhesive properties of the drug, many pharmaceutical compounds are not suitable for administration by known transdermal drug delivery systems. In these cases, when transdermal drug delivery is attempted, the drug can be found to accumulate on the outer surface of the skin and is unable to penetrate the skin into the bloodstream. An example of this has been insulin, which has been found difficult to administer by transdermal drug delivery.

Some of the most critically needed agents are currently administered through injection or oral dosage forms, which can have several disadvantages. In particular, chemotherapeutic agents are administered in exaggerated doses due to their need to be protected from degradation in the gastrointestinal tract. Many of the key HIV treatments require a cocktail of drugs in solid dosage form that is taken orally several times a day to be effective. Due to the extensive dosing requirements, and the lack of ability of the drug molecule to remain stable in the transdermal form, these drugs are not suitable for administration by known transdermal drug delivery systems. Furthermore, the unsuitability of many drugs for conventional transdermal delivery can be attributed to the low bioabsorption rate of the drug through the skin layers.

In general, conventional transdermal drug delivery methods have been found to be suitable only for low molecular weight agents such as nitroglycerin for angina relief, nicotine for smoking cessation therapy, and estradiol for estrogen replacement in postmenopausal women. alcohol. Macromolecular agents such as insulin (a polypeptide used in the treatment of diabetes), erythropoietin (used in the treatment of severe anemia), and gamma-interferon (used to enhance the immune system's ability to fight tumors) are all in use Compounds that are not normally effective when transdermal drug delivery methods are known.

However, energy, such as ultrasound energy, can be used to enhance the transdermal delivery of certain drugs. While the terms "ultrasound" and "ultrasound" are used here in their ordinary meaning, at least one source defines "ultrasound" as a mechanical pressure wave having a frequency above 20 kHz, H. Lutz et al., Manual of Ultrasound 3-12 (1984). Ultrasound can be generated by vibrating a piezoelectric crystal or other electromechanical element by passing an alternating current through the material. The use of ultrasound to increase the permeability of the skin to drug molecules has been referred to as sonophoresis or phonophoresis.

The aforementioned methods for using ultrasound to enhance transdermal drug delivery need to be used in the setting of clinical ultrasound delivery, such as a doctor's office, hospital or clinic. Furthermore, the times used to deliver measurable amounts into human skin using these methods range from 10 minutes to 24 hours. In this case, from a patient administration standpoint, a simple injection is actually more desirable than a transdermal drug delivery therapy using ultrasound. This approach is undesirable since it requires the patient to be present in a clinic setting and remain on the treatment table while ultrasound therapy is used to deliver medication.

While certain ultrasound frequencies are known to be used in certain applications for enhanced delivery of certain drugs, the results in these applications have been largely disappointing. In many cases, the drug delivery pathway utilized enables an initial dose of drug to penetrate the skin, but when longer periods of ultrasound are applied to the same location on the skin, the delivery rate drops or drops to zero.

Exposure to ultrasound is continuous or pulsed to reduce heating of the biofilm. The depth of penetration of ultrasound energy into living soft tissue is inversely proportional to frequency, therefore high frequencies have been suggested to improve drug penetration through the skin by concentrating the effect on the outermost layer of the skin (the stratum corneum). Medical agents in acoustic transdermal delivery may require variable frequency and intensity to deliver therapeutic quantities of the drug to the patient. Variables such as the fat content and mass of a particular patient tissue through which the drug will be delivered alter the frequency and intensity requirements to obtain an effective dosing regimen.

A portable programmable device and method for ultrasound-enhanced substance delivery across the body surface of a patient has not been disclosed. Due to the inefficiency and lack of safety of previous ultrasound methods, no useful device for ultrasound-assisted transdermal drug delivery has been proposed.

In the past, little effort has focused on designing a transdermal patch suitable for ultrasonic drug delivery. It is known to use an ultrasonic applicator or sonicator that is applied to the skin tissue while concomitantly focusing the target drug on the tip of the sensor and on the skin surface. (P5 line 10-11). This method of ultrasonic drug delivery is not believed to be feasible in commercial applications. Other examples (in which the skin is pre-sonicated and a patch is subsequently placed on the sonicated skin area) use a passive drug based on the concept of enhanced permeability induced by ultrasound transmission Delivery (P5 line15-17). It is also not commercially feasible due to the length of time to pre-sonicate the skin and other factors.

In view of the foregoing problems and/or deficiencies, the development of a device for safe enhanced skin permeability delivery for non-invasive drug delivery in a faster time frame would be a significant advance in the art. It would be another major advance in the art to provide ultrasonic programmable devices and methods that can be used with medicated patches. Additionally, patient mobility, as well as sustained release of a wide range of drugs, has so far remained an elusive goal for transdermal drug delivery devices. Therefore, the design delivery of a suitable transdermal patch to accommodate the active ultrasonic transdermal delivery method is helpful to achieve a commercial ultrasonic drug delivery device.

Contents of the invention

A system adapted to be secured substantially adjacent to a surface of a patient's body for delivery of at least one substance across and into the surface comprising: at least one aperture for receiving at least one ultrasonic transmission, the at least one substance is releasably secured generally adjacent the at least one aperture; and an acoustic wave member positioned in relation to the at least one aperture to effect delivery of the at least one substance across the body surface of the patient.

Description of drawings

The invention will be better understood in connection with the non-limiting accompanying drawings, in which:

Figure 1 is a transdermal patch with an ultrasound generator worn by a patient, eg, on the patient's arm.

Figure 2 is an illustration of the structure of human skin.

Figure 3 illustrates a transdermal patch with the sensor on the outside of the patch.

Figure 4 illustrates a transdermal patch where the patch is constructed using a liner or sealer around the edges of the patch.

Figure 5 illustrates an ultrasonic signal that alternates from a sawtooth wave to a rectangular wave.

Figure 6 illustrates a transdermal patch in which a sensor or array of sensors is embedded directly within the patch.

Figure 7 illustrates a transdermal patch in which a semi-permeable membrane placed beneath the patch is used to provide a valve function to steer transmitted ultrasound waves through the patch.

Figure 8 illustrates a patch according to an aspect of the present invention.

Figure 9 illustrates a transdermal delivery device according to one aspect of the present invention.

Figure 10 illustrates a sensor coupler suitable for use with the device of Figure 9 according to an aspect of the present invention, wherein the sensor coupler is configured to couple with a cap unit containing at least one substance to be delivered .

FIG. 11 illustrates a cap unit configured to couple with the sensor coupler of FIG. 10 .

FIG. 12 illustrates an internal view of the cap unit according to FIG. 11 .

FIG. 13 illustrates an inner snap ring of the cap unit of FIG. 11 .

FIG. 14 illustrates an outer snap ring of the cap unit of FIG. 11 .

15 illustrates a top view of a transdermal delivery assembly or device according to one aspect of the present invention.

16 illustrates a bottom view of the transdermal delivery assembly of FIG. 15 .

Figure 17 illustrates a top view of a sensor coupler suitable for use with the assembly of Figure 15, wherein the sensor coupler is configured to couple with a cap unit containing at least one substance to be delivered.

FIG. 18 illustrates a bottom view of the sensor coupler of FIG. 17 .

Figure 19 illustrates a top view of an inner ring of a cap unit.

FIG. 20 illustrates a bottom view of the inner ring of FIG. 20 .

Figure 21 illustrates a top view of an outer ring of a cap unit.

FIG. 22 illustrates a bottom view of the outer ring of FIG. 21 .

FIG. 23 illustrates an exploded view of the assembly of FIG. 15 .

24A-31 illustrate results that can be achieved according to one aspect of the invention.

32A to 32C illustrate a transdermal delivery device according to one aspect of the present invention.

Figures 32D and 32E illustrate results that can be achieved according to one aspect of the invention.

Figure 32F illustrates a top-top transdermal delivery system according to one aspect of the present invention.

Figure 32G illustrates a belt-mounted transcutaneous delivery system according to one aspect of the present invention.

Detailed ways

It should be appreciated that the drawings and descriptions of the present invention have been simplified to illustrate elements that are relevant to a clear understanding of the invention, while many other elements found in substance delivery systems have been excluded for purposes of clarity. Those of ordinary skill in the art will recognize that such other elements are needed and/or required to practice the invention. However, since these elements are well known in the art, and since they would not contribute to a better understanding of the present invention, a discussion of these elements is not provided here.

The present invention relates to a patch usable with an ultrasonic drug delivery device, ideally worn by a patient.

According to one embodiment of the present invention, a transdermal patch is provided for enhanced transdermal drug delivery through the use of ultrasound. As used herein, the terms "drug" and "substance" may be used together or interchangeably, and include, but are not limited to, any substance that includes, but is not limited to, a pharmaceutical or non-pharmaceutical substance, such Drug substances can be delivered across a surface or membrane, including but not limited to tissue or other types of membranes. The use of ultrasound is particularly effective in the delivery of larger pharmaceutically active compounds where the transdermal patch is tailored to the specific needs of ultrasound excitation through the patch configuration and delivery of the pharmaceutical compound stored in the patch.

According to one embodiment of the present invention, a transdermal delivery device or patch is designed using a plurality of materials to enable the transmission of ultrasound through the patch to enable the delivery of a drug stored within the patch and in conjunction with ultrasonic drug delivery methods use. Transdermal patches may contain a substance such as, for example, a specific drug or cocktail of drugs to treat a disease or relieve pain. A sonic applicator may be placed adjacent to the patch, such as, for example, on top of the patch or in a pocket in the patch or may be included in the construction of the patch itself. When the sonic applicator is excited by an external timing circuit and driver mechanism or other electronics, it generates ultrasonic oscillations or ultrasonic transmission across the transdermal patch. The effect of the ultrasound signal energy, including but not necessarily limited to, induced vibrations within the patient's skin, enhances the absorption of the agent released from the transdermal patch through the skin into the patient's bloodstream.

In accordance with one embodiment of the present invention, the introduction of ultrasonic signals to the transdermal patch increases the types of agents that can be used in transdermal delivery systems, including macromolecular agents, nutritional solutions, and drugs that cannot heretofore be delivered by transdermal systems. protein.

According to one embodiment of the invention, an ultrasonic applicator for use with a transdermal patch, as opposed to a system that uses ultrasound to facilitate drug delivery (where the patient requires the assistance of a healthcare professional, typically in a hospital, doctor's office, or clinic) Full portability in drug delivery systems is provided.

According to one embodiment of the present invention, the system can be programmed to provide steady drug delivery or pulse timed delivery for certain drug quantities, thereby providing more flexibility and control for specific patient dosing requirements. Conventional transdermal drug delivery systems are generally steady-state release devices that provide an all-in-one universal therapy, which is not suitable for drug therapy in all patients.

According to one embodiment of the present invention, a transdermal patch may be used with an ultrasonic drug delivery device that is ideally wearable by the patient and/or is a device that uses ultrasound to control transdermal and transdermal delivery of drugs and other molecules. and/or a programmable device for transmucosal flux into the body.

According to one embodiment of the present invention, a method is provided for the non-invasive delivery of molecules, including but not necessarily limited to bioactive molecules, across the skin or mucosa by use of ultrasound and a transdermal patch.

According to one embodiment of the present invention, various ultrasound frequencies, intensities, amplitudes and/or phase modulations may be applied to control the magnitude of the transepidermal flux from the patch to achieve a therapeutic or nutritional level.

According to one embodiment of the invention, the transdermal patch is designed such that the ultrasonic energy is delivered with sufficient efficiency to allow for the permeability of the drug, and it contains an absorbent material that retains the drug in the patch until it is released by ultrasound.

According to one embodiment of the invention, a sensor or an array of sensors may be built into the patch. According to one aspect of the invention, a sensor can be removably inserted into the patch.

According to one embodiment of the present invention, ultrasound may be combined with iontophoresis, electroporation, depilatory agents and/or chemical enhancers such as surfactants to facilitate transepidermal penetration.

Other advantages and novel features of the invention will be apparent from the following description and in part will be apparent to those skilled in the art upon examination of the foregoing and/or the following.

Figure 1 illustrates one embodiment of the transdermal drug (or other desired substance) delivery system 100 of the present invention. The transdermal drug delivery system 100 comprises an ultrasonic applicator 1 placed within functional proximity of a transdermal delivery device or patch (2). The patch 2 (which contains the substance to be delivered) is placed within functional proximity to contact the exterior of the patient's skin 3, usually via a strap or other suitable stabilization device 4, wherein the strap 4 connects the ultrasonic applicator 1 and The patch 2 is fixed in the desired proximity. Power for the ultrasonic applicator 1 is provided by an electric well or other suitable power source (not shown), where the power source is ideally rechargeable and which can be placed within the strap 4 itself or Other convenient locations for stationary portable transdermal drug delivery system 100 . For example, the power supply may be contained within the ultrasonic applicator device 1 itself or provided by an external source.

See hereby co-assigned and co-pending U.S. Patent Application Nos. 09/939,435, entitled "ULTRASONICALLY ENHANCED SUBSTANCEDELIVERY METHOD," and 09/939,507, entitled "ULTRASONICALLY ENHANCED SUBSTANCE DELIVERY SYSTEM," both of which Applied on August 24, 2001, all disclosures of which are respectively incorporated herein by reference.

According to one aspect of the invention, Figure 1 illustrates usage on a patient's arm. Alternatively, the system may be placed in contact with other parts of the patient's body as determined by medical personnel or other personnel administering drugs or other substance therapy. These locations may include, but need not be limited to, the patient's chest (eg, as in the case of nitroglycerin drug delivery), abdomen, neck, back and legs.

Figure 2 illustrates the structure of human skin showing the various structures that make up the skin. According to one aspect of the invention, drug or other substance delivery can be accomplished by directing the substance down one or more hair follicles. In such an embodiment, when this delivery is achieved in the hair follicles of the skin, the rate of delivery of macromolecular drugs or other substances can be significantly increased. This effect is achieved by using ultrasound, changing it to a combined transmission incorporating sawtooth and rectangular waves. More specifically, in this embodiment, the pilosebaceous pores surrounding the hair follicle can be enlarged due to this method of substance delivery and a drug travels down the follicle to the root of the hair, where it is absorbed into the blood vessels directly below the root of the hair In the blood stream in the net. Compared to the amount of matter achieved by simply using cavitation at the skin surface (which results in microporation of the skin tissue) or by simply allowing the drug to accumulate on the skin and travel through the open lenticels, this material path can be achieved in Ultrasound transports larger quantities of substances.

In one embodiment, for the purpose of enhancing the penetration of a substance (e.g., a pharmaceutical compound (drug) contained in a patch) through a tissue (such as the skin or mucous membrane or other membrane) and into the patient's bloodstream, The patch 2 may be subjected to ultrasound. The ultrasonic drug delivery system 100 can be programmed to deliver continuously (herein referred to as "sustained release") or intermittently (hereafter referred to as "pulsatile release") a pharmaceutical compound, which has been deemed more appropriate for a particular patient. medication or other therapies.

Figure 5 illustrates an embodiment of an ultrasonic signal generating the enhanced substance transport of the present invention. The signal of Figure 5 uses a combination of sawtooth and rectangular waves. In this embodiment, the preceding sawtooth wave achieves homogenization of the drug contained in the patch, and the subsequent rectangular wave delivers ultrasonic energy to the skin surface for dermal delivery.

As noted above, Figure 2 generally illustrates the typical structure of human skin. Examples of pathways through the skin into the bloodstream include:

1. Break through the cuticle.

2. Let the medicine pass through the pores of the skin.

3. Make the medicinal agent pass through the skin to the root of the hair along the pores of the pilosebaceous gland, and from there enter the vascular network at the base of the root of the hair.

In one embodiment of the present invention, transdermal drug delivery is achieved by utilizing drug pathways associated with the porosity and follicular system on the patient's skin. In one embodiment, the ultrasound frequency, intensity level and waveform dynamics can be adjusted to allow the drug to pass first through the hair follicle pathway and second through the pores in the skin surface (but not necessarily directly through the stratum corneum) Drug delivery is maximized. It is believed that the amount of energy required to penetrate the stratum corneum is excessive and also damaging to fatty tissue. This transmission through the patch and through the skin follicles and pores in embodiments of the present invention can be enhanced by using either or both of the following forces that can be applied on the skin surface:

1. First, in one embodiment, applying pressure or tension to the skin surface shrinks the skin so that the drug pathway becomes more apparent. Referring to Figure 1, a strap can be seen securing the device to the patient's arm. In addition to securing the device to the patient's body, the strap exerts pressure on the surface of the skin, thereby contracting the skin. It is believed that the contraction provided by the taut bandage achieves skin permeability by: 1) exerting downward pressure on the skin perpendicular to the skin surface; 2) stretching the skin such that pores and/or pilosebaceous glands The lenticels of the pores are easier for drugs to pass through; and/or 3) change the location of fat or other tissue under the outer skin layer, thereby enhancing transepidermal delivery, thus compared with the hope of using too much cavitation energy to the skin surface. This provides a more adequate route for drug delivery than that obtained by prior art methods that penetrate the stratum corneum.

2. Second, applying a force on the skin surface, where the force is the pressure generated by the ultrasound signal. It is believed that the use of alternating waveforms minimizes the amount of energy delivered to the skin surface while also providing a pressure wave effect on the skin, thereby enhancing drug delivery across the hair follicles and poropore system. Referring to Figure 5, one embodiment uses a waveform that alternates from sawtooth to rectangular. The amplitude and intensity of the waveform are believed to contribute to the homogenization of the drug contained within the transdermal patch (as seen in Figures 3 and 4) (which contributes to the size of the microspheres of the active pharmaceutical substance within the patch ( beadletsize) miniaturization) and drug delivery across the skin. It is believed that the short, pointed portion of the sawtooth ultrasound waveform in the sawtooth shape helps homogenize the drug without creating disruptive frequencies and cavitation of the drug. After conversion to rectangular waves, ultrasonic transmission is used to massage and open up the fatty tissue surrounding hair follicles and sweat pores. Drugs permeated from a transdermal patch are in monomeric form and/or are reduced in droplet size so that they are sized more suitable for passage through the skin. In one embodiment, the droplet size can be reduced below about 50 angstroms. The rectangular waveform helps to "push" the drug through the pores and along the hair follicle, where it travels to the root of the hair and directly through the vascular network into the bloodstream.

Ultrasound parameters (which can be varied to improve or control penetration) include, but need not be limited to: (1) frequency, (2) intensity, (3) time of exposure and/or (4) waveform of the ultrasound. All of these parameters can be modulated synchronously in a complex fashion to increase the effectiveness or efficiency of ultrasound when it comes to enhancing the flux of transepidermal molecules into or out of the body.

Since ultrasonic waves attenuate rapidly in air, a coupling agent (such as a non-pigmenting, non-irritating and slow-drying coupling agent with the lowest achievable absorption coefficient) can be used to effectively absorb the ultrasonic energy from the ultrasonic transducer. sent to the skin. They can also act as coupling agents when chemical enhancer fluids or anti-irritants or both are used. For example, glycerol, used as a counter-irritant, may also serve as a coupling agent. If desired, additional components may be added to the enhancer fluid to increase ultrasonic transmission. In one aspect of the invention, resonance responsive gels can be used to further enhance drug delivery across the skin. In addition, maintaining the drug in a sterile and non-degradable form can be used to enhance biological activity.

In one embodiment of the invention, a transdermal patch 2 may be used with a sonic applicator 1 to achieve ultrasound-assisted transdermal delivery of a desired substance. In detail, the contact between applicator 1 and patch 2 can be adjusted to ensure efficient energy transfer. The materials used to construct the patch can be chosen to maintain the strength and power output of the ultrasound transmission from the transducer through the transdermal patch. The invention is especially suitable for the delivery of macromolecular substances. For example, insulin has a large molecular size and forms hexamers typically larger than 50 Angstroms, making it difficult to penetrate through the pores of the skin. When stored, insulin molecules tend to clump together. Insulin stored in one pocket of the patch would therefore tend to agglomerate into an even larger drug mass size, reducing the potential for transdermal delivery.

To help alleviate this problem and keep the drug at a size small enough for skin delivery, the waveform of the ultrasonic signal delivered by the applicator 1 may alternate from time to time from a sawtooth to a rectangular waveform. Figure 5 illustrates the concept of alternating waveforms, where a sawtooth waveform is more effective at homogenizing the drug within the patch, when the waveform of the ultrasound is switched to a rectangular wave, resulting in improved skin delivery. In a sawtooth waveform, short periods result in high energy, and short-term pressure amplitudes, which cause vibrational effects with the target medicinal substance. This vibration has low heat and has the effect of mixing or homogenizing the medication in the patch. Smaller bead sizes are made possible by the sawtooth waveform.

Referring now to Figures 3 and 5, when the acoustic wave transmission is converted to the induced square wave, more energy is released across the patch, thereby forcing the homogenized drug through the semi-permeable membrane 13 (which can be as part of a patch affixed to the skin surface). There the intensity of the acoustic transmission acts directly along the orifice of the hair follicle shown in FIG. 2 . The rectangular waveform allows the pores directly along the follicle to "open" and become more receptive to drug delivery. The deposited drug travels down the hair follicle through the epidermis to the base of the follicle and is deposited directly into the blood stream in the vascular network of the skin. From there, the deposited drug circulates through the body.

Referring now to FIG. 1 , it can be seen that the transdermal patch 2 is first placed within functional proximity, such as, for example, in contact with the patient's skin 3 . In one embodiment of the present invention, the patch 2 can be attached to the skin 3 by adhesive or other suitable methods. The sonic applicator 1 may be placed within functional proximity to the patch 2, such as, for example, in contact with the patch 2, such that the applicator 1 generates an energy signal, such as an ultrasonic signal, wherein the signal Transdermal patch 2 across under sonic applicator 1 . The substance contained within the transdermal patch 2 can be homogenized to a smaller droplet size, which tends to more easily diffuse the substance into and through the skin. Ultrasound signals can also be achieved by disrupting and/or disrupting skin lipids to allow passage of the delivered substance. Alternatively, follicular channels may serve as substance delivery channels. Regardless of the mechanism, substances under the influence of the ultrasound signal penetrate the skin surface, travel through the layers of skin and fatty tissue, and are eventually absorbed into the patient's bloodstream and/or tissues.

Figure 3 illustrates one embodiment of a transdermal patch 2 of the present invention, referred to herein as "Patch A". A transdermal patch 2 is constructed using a backbone or substrate material 10 into which a portion or hole has been created, on top of which an ultrasound membrane 11 is integrated. The release film 12 seals the patch 2 until use. Release film 12 may be constructed of any suitable material including, but not limited to, UV-resistant, antistatic polyethylene film (50 microns thick) available from Crystal-X Corp., Sharon Hill, PA. At the bottom of the patch 2 there is a semi-permeable membrane, such as a membrane or membrane 13, which comes into functional proximity to the skin, such as in direct contact with the skin in use. Inside the patch 2, an absorbent pad 14 immobilizes the desired drug or pharmaceutical compound 15. Ultrasound signals are conveyed through the ultrasound membrane 11 and pass through the patch 2 by first passing through the absorbent pad 14 . A drug or other substance 15 is contained within the absorbent pad 14 until released by an ultrasonic signal or other means. The substance then passes through the semi-permeable membrane 13 and is deposited on or across the patient's skin surface.

Figure 4 illustrates another embodiment of a patch 2 of the present invention, referred to herein as "Patch B". A liner 16 is placed between the backbone 10 and the absorbent pad 14 . Pad 16 may be composed of any suitable material such as, for example, synthetic rubber. The liner 16 forms a reservoir or well over which the absorbent pad 14 is placed. When pressed against the skin, the liner 16 forms a barrier that helps to limit moisture and air from traveling under the patch and interfering with the ultrasound signal strength. Alternatively, a sealant compound, ultrasonic glue or other suitable material may be used in or in place of the liner 16 to provide a seal around the border of the patch 2 to provide moisture protection, prevent leakage of substances or medications from the patch, And prevent air from getting under the patch.

Referring now to Figure 6, the sensor 18 may be incorporated directly into the patch 2 or any other suitable location. A single sensor may be used or an array of ultrasonic sensors may be required in such a configuration.

FIG. 7 illustrates the underside of the patch 2 showing the well 17 and the semi-permeable membrane 13 above the absorbent pad 14 . Alternatively or additionally, an occlusive liner or compound 16 may be placed in the well 17 below the patch 2 .

Referring now to FIG. 8, in accordance with one embodiment of the present invention, a patch or system 2 is provided which is adapted to be secured substantially adjacent to a body surface of a patient to enable at least one substance to pass through the body surface and into the patient. delivery. The system 2 may comprise a substrate layer, substrate material, backbone or backbone material 10 and at least one aperture 19 formed in the substrate layer 10 for receiving at least one ultrasonic transmission. System 2 may further comprise a pad, such as an absorbent pad 14 , for releasably securing at least one substance substantially adjacent to the at least one aperture 19 . Acoustic components (such as acoustic membranes or membranes 11) can be arranged according to the at least one hole 19 to associate at least one transmission with at least one substance, thereby realizing the described at least one substance passing through the patient's body surface. delivery. A semi-permeable membrane, such as a membrane or membrane, or valve layer 13 may be provided as appropriate.

In one embodiment of the invention, the ultrasonic signal is transmitted using a combination of sawtooth and rectangular waves as depicted in FIG. 5, which is believed to first homogenize the substance 15 in the patch 2, And then skin delivery can be achieved once the substance 15 is deposited on or across the skin surface. It is not necessary to use a coupling agent between the skin and the semi-permeable membrane.

According to one aspect of the invention, the substance 15 released from the absorbent pad 14 can collect on the surface of the skin. This aggregated material can be used to further improve acoustic wave transmission by acting as an acoustic wave coupling agent. Accumulated material can be reabsorbed by absorbent pad 14 in accordance with one aspect of the present invention.

Referring again to FIGS. 3 and 4 , the acoustic membrane 11 may be constructed of any suitable resonance compatible material that allows acoustic waves emitted from the transducer 18 to be transmitted through the acoustic membrane 11 and subsequently through the absorbent pad 14 and thereafter. The patch 2 is applied to and/or passed through the patient's skin. The acoustic membrane 11 may be composed of any suitable resonance compatible material that will conduct ultrasonic transmission without unduly reducing the effects produced by the conduction of frequency or intensity potentials. Suitable resonance compatible materials for the acoustic membrane 11 may include, but are not limited to, polyvinyl chloride plastic films such as, for example, those sold as ^Saran® from the Dow Chemical Company of Midland, MI, which include, but need not limited to): models Dow BLF-2014, Dow BLF-2015, Dow BLF-2023, Dow BLF-2050, Dow BLF-2052, Dow BLF-2057, and Dow BLF-2080; and polyester films such as those available from Teijin Films Div , DuPont's Mylar(R ⁾ films of Wilmington, DE, including, but not necessarily limited to: models M30, M33, M34, D887, MC2, and SBL-300. Polyvinyl chloride film has been found to be an effective acoustic diaphragm material, however many other materials serve similar functions. The material of the patch 2 can be selected or fabricated for resonance compatibility to have the desired ultrasound frequency and intensity to be used for the skin delivery kinetics of a particular substance or drug.

In one embodiment of the present invention, acoustic membrane 11 may be adhered to absorbent pad 14 using a suitable resonance compatible material, including, but not limited to, a flat layer polyepoxy. A suitable material is polyurethane such as Uralite ^(R) available from HB Fuller Company of St. Paul, MN.

The absorbent pad 14 may consist of any suitable material, such as non-woven cellulose fibers or any similarly functioning material, which will absorb the drug 15 or hold the drug 15 during storage in the patch 2, but when the ultrasonic signal is transmitted The drug 15 is also released after passing through the patch 2 . Other possible materials may be used including, but not limited to: natural sponge, fused silica, and various woven and non-woven materials. Examples of suitable materials include (but are not limited to): CoTran 9729, a non-woven polypropylene material available from 3M, St. Paul, MN; Pop-Up Compressed Sponge available from Clipper Mill, San Francisco, CA; Sponge) (76% cellulose, 7.7% polyol, and 15.5% NaCl); Microdon Web, a non-woven polyester fiber blend available from 3M, St. Paul, MN, model M- 261420025; Available from Buckeye Absorbent Pridycts Products Memphis, TN, a cellulose mat containing wood pulp and ethylene vinyl acetate-based synthetic latex Vizorb#3010,,; and a kind of wood-containing pulp available from Buckeye Absorbent Products Memphis, TN and cellulose mat Vicell #6 009 based on synthetic latex of ethylene vinyl acetate.

A semi-permeable membrane 13 may be placed at the bottom of the patch 2 such that it is in direct contact with the patient's skin. This semi-permeable membrane 13 can act as a valve so that the drug 15 released from the absorbent pad 14 can pass through the semi-permeable membrane 13 only under the active generation of ultrasound waves. In the absence of ultrasound signals, the semi-permeable membrane 13 is capable of preventing substantial amounts of drug from permeating the membrane to or across the patient's skin surface. The valve action of the semi-permeable membrane 13 can provide a means of controlling the dose delivered to the patient. It is believed that the sonicated portion of skin remains permeable to delivered substances, such as drugs, for a period of time after the ultrasound signal has been terminated. In this case, if the drug will reach the skin, the skin can continue to absorb the drug after the ultrasound signal stops. Assuming a steady delivery rate can be achieved using the active ultrasound signal, the delivery of the appropriate dose will be proportional to the number of seconds or minutes the active ultrasound signal is present on the skin surface. In this way, the delivered drug dose level may correspond to the timing of the active ultrasound signal.

If there is continued skin penetration after the active ultrasound signal ceases, it can be difficult to determine the exact dose actually delivered to the patient. A valve patch can thus be provided which effectively shuts off drug delivery after the ultrasound signal is terminated. A sonically reactive semi-permeable membrane 13 may be used at the base of the patch 2 to ensure that the patch 2 will only deliver the drug in the presence of an ultrasonic signal, for example by means of the sonic applicator device 1 depicted in FIG. Timing circuit to deliver the appropriate dose at regular intervals.

Suitable elastomeric materials that change properties when exposed to changes in pressure or temperature may be used to construct the semi-permeable membrane 13 . In one embodiment of the present invention, any suitable material may be used as the semi-permeable membrane 13, including, but not limited to, natural sponges and perforated polymeric films. It is believed that the ultrasonic signal creates a cavitation effect in the polymer film, thereby enlarging the diameter of the perforated holes in the film, thereby making the film more permeable. In the absence of an ultrasound signal, the elasticity of the membrane will cause it to return to its original configuration and reduce the diameter of any pierced holes, thereby blocking further transport of macromolecules contained in the patch 2 from the patch 2 to the skin.

According to one embodiment of the present invention, the semi-permeable membrane 13 may be constructed of any suitable semi-permeable material that does not allow the solution containing the drug to diffuse across the membrane in the absence of an ultrasonic signal, but allows the drug to The solution diffuses across the membrane.

According to one embodiment of the present invention, semi-permeable membrane 13 may be constructed from any suitable thermoplastic material. This material changes properties when subjected to a temperature increase caused by ultrasonic vibrations, and returns to its original state when the ultrasonic signal ceases. According to one embodiment of the present invention, the semi-permeable membrane 13 may be constructed of any suitable thermoplastic material that changes its permeation properties when subjected to an ultrasonic signal, thereby allowing movement of the drug across the membrane, and substantially recovers after the ultrasonic signal ceases. to its initial permeability state.

According to one embodiment of the present invention, the semipermeable membrane 13 may be constructed from any suitable ionomer (ion-containing polymer), including, but not necessarily limited to, those ionomers that function as thermoplastic elastomers. According to one embodiment of the invention, suitable ionomers include, but need not be limited to, ethylene-co-methacrylic acid copolymers (such as, for example, available from Dupont of Wiltnington, DE as ^Surlyn® and sold film).

After the transdermal patch 2 has released the composition of the drug 15, the patch 2 can be replaced by a new patch 2. The new patch 2 is then used for another cycle of drug delivery. Alternatively, additional quantities of substances or pharmaceutical agents may be inserted into the patch 2 by suitable means to effectively "refill" the patch. In one embodiment, when replacing the patch 2, it can be detached from the sensor assembly 18 or other source of ultrasound signals.

According to one embodiment of the invention, patch 2 is attached to one or more sensors 18 by a sonic adhesive or coupling agent. The sonic adhesive can be any suitable material including, but not limited to, a mineral oil. An example of a suitable mineral oil is Draecol 9 available from Eastern Chemical in Philadelphia, PA.

Alternatively, for example, a crease at the top of the transdermal patch 2 could be used to slide the sensor 18 into the topmost portion of the patch. The sensor 18 can be built directly into the structure of the patch as shown in FIG. 6 .

The backbone 10 of the patch 2 may be made of any suitable material including, but not limited to, polyolefin film or polyvinyl chloride. An example of a suitable material is Polyvinyl Chloride Foam Tape 9772-L (available from 3M, St. Paul, MN) and Foam Tape Model 3M 9773 (available from 3M, St. Paul, MN). Paul, MN, a polyolefin foam tape with an adhesive backing). The backbone material 10 may also have an adhesive, such as, for example, a pressure sensitive acrylic adhesive used on 3M 9772-LFoam Tape (available from 3M, St Paul, MN), which enables the patch 2 to Adheres to the patient's skin surface.

According to one embodiment of the present invention, a backing member 10 comprising Model Number 9772-L FoamTape (3M, St. Paul, MN) contains at least one aperture covered by a sonic membrane 11 which Acoustic films include: Saran ^(R) film, model Dow BLF-2014 (Dow chemical Co., Midland, MI) or Mylar ^(R) film, model M34, DuPont Teijin Films, Wilmington, DE. At least one absorbent pad 14 comprising a cellulosic material (Model Vicell ^(R) #6009, Buckeye Absorbent Products, Memphis, TN) may be placed such that ultrasonic energy is transmitted through the acoustic membrane 11 to the absorbent pad 14. Insulin solution ( ^Humulin® , Eli Loll, Indianapolis, IN) contained on or within the absorbent pad 14 can move through the semipermeable membrane 13 comprising ^Surlyn® membrane (Dupont, Wilmington, DE) when an ultrasonic signal is present, and delivered to the patient. A release film 12 comprising UV-blocking antistatic polyethylene film (50 microns thick) (Crystal-XCorp, Sharon, PA) was available.

According to an embodiment of the present invention, the patch 2 allows the ultrasonic signal transmission to completely pass through the patch 2 . Therefore, there is a need to minimize the attenuation of the ultrasound signal as it travels through the material of the patch 2 . Particular attention needs to be paid to the fact that cavities containing eg air, gas or moisture located in the absorbent material used in the patch 2 can later act on the frequency and/or intensity of the transmitted ultrasound signal. To facilitate improved ultrasound transmission through the patch, the absorbent material may be vacuum lyophilized to remove entrapped air from within the absorbent material. In this method, the material is frozen by freeze-drying, and then the material is vacuum-dried. One effect of freeze-drying is to reduce the amount of trapped air within the fabric of the absorbent material, thereby making the absorbent material more resonantly compatible with the frequency and intensity of ultrasonic transmission and improving its attenuation properties.

According to an embodiment of the present invention, the absorbent pad material can be soaked in 0.9% sodium chloride aqueous solution before freeze-drying treatment. Pretreatment with saline solution leaves sodium chloride residues in the absorbent material. The salt residue acts as a humectant, which attracts moisture and thus maintains some moisture within the absorbent pad. Preventing the absorbent pad from drying out can allow the drug stored in the pad to remain in solution, preventing loss of moisture that can cause the drug solution to become increasingly concentrated. Concentration of the drug solution can be avoided because it can cause the active drug to build up or precipitate out of solution, thereby hindering drug delivery.

Suitable materials for absorbent pads may have one or more of the following properties:

1) High absorption of selected drugs in emulsion or solution form.

2) The absorbent material is inert to the selected drug, or to the excipients or preservatives used in the solution form of the drug, during extended storage periods.

3) The absorbent material resists degradation when exposed to ultrasound and does not release contaminants into the stored drug.

4) The absorbent material is substantially free of metallic, organic or inorganic contaminants.

5) The absorbent material is non-irritating to human skin and remains stable when interacting with human sweat.

6) The absorbent material is stable in storage form for a year or more and resists degradation over time after being saturated with drug.

7) The absorbent material can consist of natural or synthetic materials.

According to one embodiment of the invention, the absorbent material is a superabsorbent, which is defined as a material capable of absorbing approximately fourteen (14) or more times its own weight in liquid. This superabsorbent material provides the pad with the ability to store the drug in dilute solution or suspension. This is especially important for polypeptides such as insulin, which are believed to form multimeric structures when concentrated in solution. Preventing the absorbent pad from drying out, and thus maintaining the insulin in a dilute solution, maintains the insulin in the monomeric form that is most easily transported out of the patch and across the skin.

According to one embodiment of the invention, the absorbent material contains functional groups capable of cross-linking with drugs. In Patch 2, this crosslinking can be used to stabilize the drug for storage. When an ultrasound signal is applied through the patch 2, upon reaching the absorbent material, the ultrasound signal causes the breakdown of the cross-links so that the drug is released from the absorbent material and can be freely delivered to a patient.

According to one embodiment of the present invention, the absorbent material may be formed from a material containing an appropriate amount of cross-linking points, such that the absorbent material is capable of forming cross-links with the drug, but does not form cross-links that disrupt the natural structure of the drug, and allows the absorbent material to The cross-link is released after the ultrasonic signal, so that the drug is no longer bound by the absorbent pad 14 and can be freely delivered to the patient's tissue.

According to one embodiment of the invention, the absorbent material and the drug are cross-linked by hydrogen bonding. According to one embodiment of the invention, the absorbent material contains functional groups capable of forming hydrogen bonds with functional groups of a polypeptide drug such as, for example, insulin. In this case, hydrogen bonds serve to stabilize the drug's structure. Upon exposure to an ultrasound signal, the hydrogen bonds cross-linking the drug to the absorbent material are disrupted, but not the hydrogen bonds forming the native secondary structure or other aspects of the structure of the polypeptide.

Table 1 lists at least some materials that may be used in the construction of absorbent pad 14:

Table 1

Examples of materials suitable for absorbent pad 14

Cellulose Fiber Mat Cotton

Natural Sponge Cloth Woven

Polyurethane Foam Polyisocyanate Foam

Nonwoven Fabric Fused Silica

Starch Corn Flour

Wood pulp fiber Collagen mat

Polymethacrylate Polyvinyl Alcohol

Polyethylene tetrahydropyrrole Polyacrylic acid

Poly(2-Hydroxyethyl Acrylate Polyacrylamide

Polyethylene Glycol Polylactide (PLA)

Polyglycolide (PGA) Poly(lactide-co-glycolide)

Polycarbonate Chitosan

Poly(N-isopropylacrylamide)

Copolymer formulation of polymethacrylic acid and polyethylene glycol

Copolymer formulation of polyacrylic acid and poly(N-isopropylacrylamide)

Hydrogels such as polyacrylamide, poly(propylene oxide

Polypropylene glycol and propylene oxide addition polymer polyol family for gel materials, such as polypropylene glycol and propylene oxide addition polymer-chitosan hydrogel

Silica gel

Any other natural or synthetic material designed to absorb pharmaceutical compounds and release the drug upon ultrasonic excitation

According to one embodiment of the present invention, the absorbent compound may be a non-woven material having a suitable amount of functional groups capable of cross-linking. When the absorbent material is in contact with the drug, the functional groups of the absorbent material form a cross-link with the drug, thereby stabilizing the structure of the drug when there is no ultrasonic signal. When ultrasonic signals are transmitted through the patch to the absorbent material, the cross-links are broken, allowing the drug to be released from the absorbent material without contamination of the drug or disruption of the drug's natural structure.

According to one embodiment of the invention, the absorbent material is treated by freezing followed by vacuum drying. The absorbent material is freeze-dried to reduce the amount of contaminants such as air or moisture that would become trapped in the absorbent material. This contaminant can interact with the functional groups of the absorbent material, thereby preventing these functional groups from forming cross-links with the drug. After freeze-drying, these contaminants are removed, thereby releasing the cross-linking sites of the absorbent material so that these sites are free to form cross-links with the substance to be delivered. Additionally, freeze-drying removes contaminants that might otherwise react with or contaminate the drug.

According to one embodiment of the present invention, the absorbent material is capable of retaining the drug in the absence of an ultrasound signal, is capable of releasing the drug after being excited by the ultrasound signal, and has absorbing properties such that any excess drug remaining on the skin surface after the ultrasound signal is terminated reabsorbs into the the absorbent pad and does not release the excess drug until another ultrasonic signal is transmitted to the absorbent material. This function of the absorbent material allows precise control of the delivered drug dose via the parameters of the ultrasound signal, and eliminates the need for a semi-permeable "valve" membrane to control the dose. According to one aspect of the present invention, a material capable of absorbing 1 to 4 times its own weight in drug solution can provide suitable absorption/release/reabsorption characteristics, which can enable controlled dose release by ultrasound. Absorbency can be adjusted by utilizing different types and combinations of fibers to produce absorbent materials. For example, cellulosic materials can be produced from fibers derived from various woods (eg, "hardwood" versus "softwood") that have different absorbency properties.

According to one embodiment of the invention, when the ultrasound signal is transmitted through the patch 2, the signal massages the pores immediately surrounding the hair follicle, thereby increasing the permeability of such pores. The ultrasonic signal enhances the transport of the drug 15 stored in the absorbent pad 14 in the patch 2 across the semipermeable membrane 13 and deposits the drug 15 onto the skin surface where it travels along the hair follicle to the root of the hair and into the vascular network And be absorbed into the human body.

According to one embodiment of the present invention, the ultrasonic transmission may have a frequency in the range of about 20 kilohertz to about 10 megahertz. The intensity of the ultrasonic transmission may range from about 0.01 W/cm2 to about 5.0 W/cm2. Variations in frequency and intensity levels may require changes in the materials used in the construction of the transdermal patch 2 to accommodate optimum performance in drug delivery and valve function achieved by the semi-permeable membrane 13 .

According to one embodiment of the present invention, while a transition from a sawtooth to a rectangular waveform has been described, the known sinusoidal waveform is also valid as a drug delivery waveform for ultrasound transmission.

The devices and methods according to the invention are suitable for delivering a variety of substances to a patient. As described in more detail herein, substances can be delivered, for example, transcutaneously, percutaneously, intralumenally, and within parenchymal tissue sites, wherein in all cases, by application of ultrasound or sonic energy Acoustics, on the other hand, facilitate the absorption of the substance or its pharmacologically active moiety into the tissue under or around the tissue. The substance may be in any suitable form, including but not limited to liquids, gels, porous reservoirs, inserts, or the like, and the substance or pharmacologically active portion thereof may, for example, treat or alleviate an existing disease, or Preventive prevention or suppression of another disease in a patient. The effect of a substance can be local (such as providing anti-tumor therapy), or it can be systemic. Suitable drugs include, but are not limited to, a wide variety of compounds that are normally delivered across the skin and other body surfaces or into parenchymal tissues.

In general, such medications may contain or incorporate substances including, but not limited to: anti-infectives such as antibiotics and antivirals; analgesics and painkiller mixtures; anorectics; anthelmintics; Rheumatic agent; Asthma agent; Anticonvulsant; Antidepressant; Agent for diabetes; Antidiarrheal agent; Antihistamine; Antiinflammatory agent; Antimigraine agent; Antinausea agent; Antineoplastic agent; Antiparkinsonian agent Antipruritics; Antipsychotics; Antipyretics; Anticonvulsants; Anticholinergics; Sympathomimetic agents; Xanthine derivatives; Cardiovascular agents, including but not limited to potassium and calcium channel antagonists, beta receptors Blockers, and antiarrhythmics; antihypertensives; diuretics; vasodilators, including conventional coronary, peripheral, and cerebral artery dilators; central nervous system stimulants; cough and cold preparations, including Decongestants; hormones, including but not limited to steroids (including but not limited to estradiol) and corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; sedatives; and sedatives agent. The method of the present invention can deliver ionized and non-ionized drugs, as well as high molecular weight and low molecular weight drugs.

Protein and polypeptide drugs represent a class of drugs suitable for use with the presently disclosed invention. Such drugs generally cannot be administered orally because they are often destroyed in the gastrointestinal tract or metabolized in the liver. Furthermore, due to the high molecular weight of most polypeptide drugs, known transdermal delivery systems are not always effective.

Common examples of pharmaceutical or nutritional compounds that may be contained within the transdermal patch 2 of the present invention include (but are not limited to): acetaminophen, antibiotics, aspirin, corticosterone, erythromycin, ibuprofen, insulin, Nitroglycerin, nicotine, steroids (including but not limited to progesterone), estrogens (eg, estradiol), and vitamins. Suitable forms of insulin include, but need not be limited to, ^Humulin® R and ^Humulog® , both commercially available from Eli Lilly Company, Indianapolis, IN. Any other substances including, but not limited to, medicinal and/or nutraceutical compounds for nutraceutical, medicinal or pharmaceutical purposes, and any mixtures thereof, may also be utilized. It may also be desirable to use the methods of the present invention with drugs for which skin penetration is relatively low or which result in a long lag time. It has been found that the administration of the ultrasound signals described herein significantly reduces the lag time involved in the transdermal administration of most drugs.

The combined use of ultrasound signals and iontophoresis, the application of electrical current to the skin, has been attempted in various drug delivery procedures. In some examples, the ultrasound signal is used with iontophoresis, while in other examples the ultrasound signal is pre-treated with iontophoresis. Applicants have indicated that iontophoresis can be used in conjunction with the device of the present invention as a method for enhancing the delivery of molecules across the skin.

The use of chemical substances, commonly referred to as chemical enhancers, can also enhance drug delivery in the present invention.

According to one embodiment of the invention, a security feature may be incorporated which indicates that the tile is empty or has already been used. The use of an ultrasound contrast agent or color forming marker within the patch that will change color (eg from green to red) upon exposure to ultrasound may be provided as a means of indicating that the patch has been used.

According to one embodiment of the invention, the transdermal patch 2 may be equipped with a biosensor capable of detecting the patient's glucose level by invasive or noninvasive methods, the data from the sensor being used to control the flow rate from the patch. Timing of administration of medicament and drug delivery.

According to one embodiment of the invention, the transdermal patch 2 can be equipped with a biosensor capable of detecting the amount of medicament actually delivered to the patient. This sensor measures the electrical resistance of the patient's skin. Delivery of a drug across the skin results in a readable change in the electrical conductivity of the skin tissue surrounding the site of delivery. Data from this biosensor can be used to record the actual amount of drug delivered from the patch to the patient.

Referring now to FIG. 9, there is illustrated a transdermal delivery device or assembly 300 in accordance with one aspect of the present invention. Such a delivery device may comprise a sensor coupler 201 comprising a sensor housing 202 inside which at least one ultrasonic sensor 18 or a sensor array 18 is placed. According to one aspect of the invention, the sensor array 18 may be a 2x2 array. The delivery device may further comprise a cap unit or patch cap 210 which houses an absorbent pad 14 containing at least one substance to be delivered. The acoustic membrane 11 may be made as part of the cap unit 210 or adhered to the cap unit 210 such that it covers the side of the absorbent pad 14 in contact with the sensor coupler 210 . According to one aspect of the present invention, the acoustic membrane 11 may be formed from a polyvinylidene chloride plastic film such as, for example, the film sold as ^Saran® , including, but not necessarily limited to, available from Dow Chemical Company of Midland, MI. Model DowBLF-2014) and build,. According to one aspect of the present invention, the acoustic membrane 11 may have a diameter of about 4.0 centimeters and a thickness of about 50 microns. According to one aspect of the present invention, acoustic membrane 11 may be constructed from a polyester film such as Mylar ^(R) film including, but not necessarily limited to, model M34 available from DuPont Teijin Films Div. of Wilmington, DE. According to one aspect of the invention, the acoustic membrane may have the following approximate dimensions: 4.0 cm (diameter) x 13 microns (thickness). The release film 12 may be formed as part of the cap unit 210 such that until removed it covers the side of the absorbent pad 14 that will be placed against a substance delivery target such as the skin of a patient. After removal of the release film 12, the absorbent pad 14 containing at least one substance can be exposed to ensure that the absorbent pad is adjacent to the substance delivery target.

According to one aspect of the invention, the cap unit 210 optionally includes a semi-permeable membrane 13 beneath the cap 210 such that the semi-permeable membrane 13 comes within functional proximity of the patient's body surface. The semi-permeable membrane 13 may be constructed of any suitable material including, but not necessarily limited to, ethylene-co-methacrylic acid copolymers (such as, for example, ^Sulphate® sold as Surlyn® from Dupont of Wilmington, DE. Membrane. According to one aspect of the present invention, the semi-permeable membrane 13 may have the following approximate dimensions: 4.0 cm (width) x 4.0 cm (length) x 50 microns (thickness).

The transdermal delivery device can be constructed such that the cap unit 210 is snapped or screw coupled onto the sensor coupler 201 to create a transdermal delivery device or assembly. Cap unit 210 and sensor coupler 201 may be connected together through the use of threaded joints, male and female connection slots, a bayonet connection type system, or other connection systems or devices (collectively referred to herein as screw couplings). The screw coupling can engage the sensor coupler 201 and the cap unit 210 by rotating or turning the sensor coupler 201 and the cap element 210 such that the coupler 201 and the cap unit 210 are substantially engaged. An example of a screw coupling with a single rotation or turn is a configuration similar to child safety caps commonly used in pharmaceutical packaging.

Electrical leads or cables 204 may be used to connect the sensor 18 to a power supply and/or control unit 400 ( FIG. 32G ), and may extend from the sensor coupler 201 .

Strap 250 may be used to secure transcutaneous delivery device 300 to the patient's body. The pressure created by the attachment of the straps 250 to the patient creates an interface between the absorbent pad 14 and the patient's body surface. The pressure created by the attachment of the straps 250 to the patient can be used to create an acoustic connection or interface between the absorbent pad 14 and the patient's body surface. The pressure created by the attachment of the straps 250 can create an interface between the absorbent pad 14 and the patient's body surface that generally prevents leakage of material from beneath the cap 210 and also generally prevents contamination of the material being delivered to the patient's body surface. .

According to an aspect of the present invention, the cap unit 210 may include internal threads, and may be screw-coupled to the sensor coupler 210 having external threads. The pressure generated by the screw coupling of the cap unit 210 to the sensor coupler 201 may establish an acoustic connection or interface between the sensor coupler 201 and the acoustic membrane 11 of the cap unit 210 . The pressure generated by the screw coupling of the cap unit 210 to the sensor coupler 201 may establish an acoustic connection or interface between the acoustic membrane 11 and the absorbent pad 14 .

Alternatively, according to an aspect of the present invention, the sensor coupler 201 may be similarly screw-coupled to the cap unit 210 .

Referring now to FIG. 10, there is shown a sensor coupler 201 suitable for use with the present invention. The sensor coupler 201 may include a housing 202 having at least one sensor cap connection groove 203 . The sensor coupler may further include an acoustic panel 205 designed to form an acoustic interface with the cap unit 210 (FIG. 9). According to one aspect of the present invention, sensor coupler 201 may be 4.0 centimeters in diameter, approximately 1.0 centimeters thick, and is manufactured by Sonic Systems, Inc. of Newtown, PA. Housing 202 may be constructed of any suitable material. According to one aspect of the invention, housing 202 may be constructed from plastic components such as, for example, Epoxy 45LV ^and Catalyst 15LV sold as Eccobond(R) from Emerson & Cuming of Billerca, MA. The acoustic panel 205 may be composed of any acoustically compatible material such as, for example, approximately 4.0 cm (diameter) x 1.0 mm (thick) stainless steel plate available from Sonic Systems, Inc. of Newtown, PA.

Referring now to FIG. 11 , there is shown a cap unit 210 suitable for use with the sensor coupler 201 of FIG. 10 . The cap unit 210 may be constructed of plastic or any acoustically compatible material. The cap unit 210 may comprise an absorbent pad 14 (Fig. 9) containing at least one substance to be delivered. According to one aspect of the present invention, the absorbent pad 14 may be constructed from a cellulose pad comprising wood pulp with an ethylene vinyl acetate based synthetic rubber such as Vicell #6009 available from Buckeye Absorbent Products of Memphis, TN.

According to one aspect of the present invention, the absorbent pad 14 has a diameter of about 4.0 cm and a thickness of 0.92 mm. Cap unit 210 may further comprise an adhesive or closure ring 213 adapted to contact the patient's skin and form a seal to substantially prevent air or contaminants from entering under or within the device and from being deposited by the transdermal delivery system Leakage or contamination of a substance on a patient's skin. According to one aspect of the present invention, the adhesive ring 213 can be constructed from a polyvinyl chloride with adhesive backing: foam tape model number 3M 9772-L available from 3M Co. of St. Paul, MN. According to one aspect of the invention, the adhesive ring 213 can be constructed from a polyolefin film with an adhesive backing: Foam Tape Type 3M 9773. According to one aspect of the present invention, the adhesive ring 213 may have the following approximate dimensions: Bore: 3.75 cm in diameter, Ring Dimensions: 0.25 cm x 1.0 mm (thick).

The cap unit 210 may have a textured surface 212 on the outer surface of the cap 210 to improve the user's ability to grip and rotate the cap 210 . According to one aspect of the present invention, cap unit 210 is approximately 4.0 centimeters (diameter) by approximately 0.75 centimeters (thickness), as provided by Definitive Design Co. of Langhorne, PA. According to one aspect of the invention, the cap unit is replaceable such that after a substance has been dispensed from the cap 210, the cap can be discarded and replaced with a new cap unit 210. Alternatively, the pad 14 can be adapted so that it can be replaced without requiring a new cap unit 210 . Either way the additional substance to be delivered can be provided without the need to replace the sensor coupler 201 . Of course, device 300 (FIG. 9) could be designed so that sensor coupler 201 (FIG. 10) could be replaced periodically, or the entire assembly 300 could be designed as a single non-reusable device.

Referring now to FIG. 12 , the cap unit 210 may be constructed by an outer snap ring 230 and an inner snap ring 220 set inside the outer snap ring 230 . According to one aspect of the present invention, the inner snap ring 220 generally holds the absorbent pad 14 in place. Referring now also to FIGS. 13 and 14 , the inner snap ring 220 may include at least one inner connector fitting or bayonet 222 and at least one outer connector fitting 221 . The outer snap ring 230 may include at least one connection groove 211 into which the outer connector joint 221 of the inner snap ring 220 may be inserted, so as to screw-couple the inner snap ring 220 to the outer snap ring 230 . The inner connector joint 222 can be fitted into the sensor cap connection groove 203 ( FIG. 10 ) to make the connection more tightly when the cap unit 210 is screw-coupled to the sensor connector 201 . According to an aspect of the present invention, the connection between the cap unit 210 and the sensor coupler 201 can form an acoustic connection between the absorbent pad 14 and the sensor connector 201 . In such a configuration, absorbent pad 14 may be secured adjacent or substantially adjacent sensor coupler 201 .

Referring now to Figures 15 and 16, there is illustrated a transdermal delivery device or assembly 300 in accordance with one aspect of the present invention. Such a delivery device may comprise a sensor coupler 201 comprising a sensor housing 202 in which at least one ultrasonic sensor 18 (not shown) or a sensor array 18 may be placed. According to one aspect of the invention, the sensor array may be a 2x2 array. The delivery device may further comprise a cap unit or patch cap 210 containing an absorbent pad 14 (shown in FIG. 32A ) containing at least one substance to be delivered. Acoustic membrane 11 (not shown) may be formed as part of cap unit 210 or it may be adhered to cap unit 210 such that it covers the side on which absorbent pad 14 is placed in contact with sensor coupler 201 . According to one aspect of the present invention, the acoustic membrane 11 may be formed from a polyvinylidene plastic film such as, for example, that sold as ^Saran® , including, but not necessarily limited to, the models available from Dow Chemical Company of Midland, MI. Dow BLF-2014) and build. According to one aspect of the present invention, the acoustic membrane 11 may have a diameter of about 4.0 centimeters and a thickness of about 50 microns. According to one aspect of the present invention, the acoustic membrane 11 may be constructed from a polyester film such as Mylar ^(R) film including, but not necessarily limited to, model M34 available from DuPont Teijin Films Div. of Wilmington, DE. According to one aspect of the invention, the acoustic membrane may have the following approximate dimensions: 4.0 cm (diameter) x 13 microns (thickness). The release film 12 may be formed as part of the cap unit 210 such that before it is removed it covers the side of the absorbent pad 14 that will be placed against a substance delivery target, such as the skin of a patient. After removal of the release film 12, the absorbent pad 14 containing at least one substance can be exposed to secure it adjacent the substance delivery target.

According to one aspect of the present invention, the cap unit 210 optionally includes a semi-permeable membrane 13 (not shown) beneath the cap 210 such that the semi-permeable membrane 13 comes within functional proximity of the patient's body surface. The semi-permeable membrane 13 may be constructed of any suitable material including, but not necessarily limited to, ethylene-co-methacrylic acid copolymers (such as, for example, ®, sold as Surlyn® from DuPont of Wilmington, DE ^] . film). According to one aspect of the present invention, the semipermeable membrane 13 may have the following approximate dimensions: 4.0 cm (width) x 4.0 cm (length) x 50 microns (thickness).

The transdermal delivery device may be constructed such that cap unit 210 and sensor coupler 201 are press fit or snapped together to form a transdermal delivery device or assembly 300 . Cap unit 210 and sensor coupler 201 may be connected together using a press-fit or snap-in connection or other suitable connection system or means.

Electrical leads or cables 204 may be used to connect the sensor 18 (not shown) with a power supply and/or control unit 400 (shown in FIG. 32G ), and may extend from the sensor coupler 201 .

A strap 250 (not shown) may be used to secure the transcutaneous delivery device 300 to the patient's body (shown in Figures 32E and 32F). The pressure exerted by straps 250 attached to the patient establishes a functional interface between absorbent pad 14 (FIG. 32A) and the patient's body surface. The pressure created by the attachment of the straps 250 to the patient can be used to establish an acoustic connection or interface between the absorbent pad 14 and the patient's body surface. The pressure created by the strap 250 attachment creates an interface between the absorbent pad 14 and the patient's body surface that substantially prevents leakage of material from beneath the cap 210 and generally prevents contamination of material delivered to the patient's body surface.

The pressure generated by snapping or pressing the cap unit 210 onto the sensor coupler 201 may create an acoustic connection or interface between the sensor coupler 201 and the acoustic membrane 11 of the cap unit 210 . The pressure created by snapping or pressing the cap unit 210 onto the sensor coupler 201 can create an acoustic connection or interface between the acoustic membrane 11 and the absorbent pad 14 .

Alternatively, the sensor coupler 201 may similarly be snapped or pressed onto the cap unit 210 in accordance with an aspect of the present invention.

Referring now to Figures 17 and 18, there is shown a sensor coupler 201 suitable for use with the present invention. The sensor coupler 201 may further include a housing 202 having at least one sensor cap connection slot 203 . The sensor coupler may further comprise an acoustic panel designed to form an acoustic interface with the cap unit 210 (FIG. 15). According to one aspect of the invention, sensor coupler 201 may be about 4.0 centimeters in diameter and about 1.0 centimeters thick, and is manufactured by Sonic Systems, Inc. of Newtown, PA. Housing 202 may be constructed of any suitable material. According to one aspect of the invention, housing 202 may be constructed from a plastic component such as, for example, Epoxy 45LV and Activator 15LV available as ^Eccobond® from Emerson & Cuming of Billerca, MA. The acoustic panel 205 may be composed of any acoustically compatible material such as, for example, approximately 4.0 cm (diameter) x 1.0 mm (thick) stainless steel plate available from Sonic Systems of Newtown, PA.

Referring now to FIGS. 19 to 22 , the cap unit 210 (shown in FIGS. 32A and 32B ) may be formed by and substantially fixed to an outer snap ring 230 (shown in FIGS. 21 and 22 ) (shown in FIGS. 32C ). shown) inside the inner snap ring 220 (shown in Figures 19 and 20). According to one aspect of the present invention, when the inner snap ring 220 is sufficiently secured within the outer snap ring 230, the inner snap ring 220 can fully secure the absorbent pad 14 in place (shown in FIG. 32A).

Cap unit 210 may be constructed from any suitable material. According to one aspect of the present invention, cap unit 210 is about 4.0 centimeters (diameter) by about 0.75 centimeters (thickness), as provided by Definitive Design Co. of Langhorne, PA. According to one aspect of the invention, the cap unit 210 is replaceable such that after dispensing a substance from the cap 210, the cap can be discarded and replaced with a new cap unit 210. Alternatively, the pad 14 can be adapted so that it can be replaced without requiring a new cap unit 210 . Either way the additional substance to be delivered can be provided without the need to replace the sensor coupler 201 . Of course, device 300 (FIG. 15) could be designed so that sensor coupler 201 (FIG. 17) could be replaced periodically, or the entire assembly 300 could be designed as a single non-reusable device.

Cap unit 210 may comprise an absorbent pad 14 (Fig. 32A) containing at least one substance to be delivered. According to one aspect of the present invention, the absorbent pad 14 may be constructed from a cellulose pad comprising wood pulp with an ethylene vinyl acetate based synthetic rubber, such as Vicell #6009 available from Buckeye Absorbent Products of Memphis, TN. According to one aspect of the present invention, the absorbent pad 14 has a diameter of about 4.0 cm and a thickness of 0.92 mm. Cap unit 210 may further comprise an adhesive or closure ring 213 adapted to contact the patient's skin and form a seal to substantially prevent air or contaminants from entering under or within the device and from being deposited by the transdermal delivery system Leakage or contamination of a substance on a patient's skin. According to one aspect of the present invention, the adhesive ring 213 can be constructed from a polyvinyl chloride with adhesive backing: foam tape model number 3M 9772-L available from 3M Co. of St. Paul, MN. According to one aspect of the invention, the adhesive ring 213 can be constructed from a polyolefin film with an adhesive backing: Foam Tape Type 3M 9773. According to one aspect of the present invention, the adhesive ring 213 may have the following approximate dimensions: Bore: 3.75 cm in diameter, Ring Dimensions: 0.25 cm x 1.0 mm (thick).

Referring now to FIGS. 19 and 20 , the inner snap ring 220 may include at least one inner connector fitting or bayonet 222 and at least one outer connector fitting 221 . Referring now to FIGS. 21 and 22, the outer snap ring 230 may include at least one connecting groove 211 into which the outer connector fitting 221 of the inner snap ring 220 may be inserted, thereby snapping or pressing the inner snap ring 220 into place and closing the inner snap ring 220 into place. The snap ring 220 is substantially fixed in the outer snap ring 230 . Of course, any suitable method of enabling the inner snap ring 220 to be snapped into and generally secured within the outer snap ring 230 may be utilized. Referring again to FIG. 23 , according to one aspect of the present invention, the inner snap ring 220 can be coupled to the outer snap ring 230 by snap or press fit to form a cap unit 210 (shown in FIGS. 32A and 32B ). The inner connector joint 222 can be fitted into the sensor cap connection groove 203 so that the connection between the cap unit 210 and the sensor coupler 201 is more tightly coupled. According to one aspect of the invention, the connection between the cap unit 210 and the sensor coupler 201 can form an acoustic connection between the absorbent pad 14 ( FIG. 32A ) and the sensor coupler 201 . In such a configuration, absorbent pad 14 may be secured adjacent or substantially adjacent sensor coupler 201 (shown in FIGS. 32A-32C ).

Reference is now made to FIGS. 24A-31 , which illustrate achievable results according to one aspect of the present invention.

Reference is now made to Figures 32A to 32C, which illustrate a transdermal delivery assembly according to one aspect of the present invention.

Reference is now made to Figures 32D to 32E, which illustrate achievable results according to one aspect of the present invention.

Reference is now made to Figure 32E, which illustrates a bench top transdermal delivery system in accordance with one aspect of the present invention.

Reference is now made to Figure 32F, which illustrates a belt-mounted transcutaneous delivery system in accordance with one aspect of the present invention.

Having described the invention in detail above, those skilled in the art will recognize that there are many variations in the design and function of the device, but it is desired to minimize such variations in design and function in this disclosure. Furthermore, while the present disclosure has a certain degree of character, it should be understood that the preferred form of the present disclosure is made by way of example and may be modified without departing from the spirit and scope of the invention as hereinafter claimed. Numerous variations can be made in details of construction and combinations and arrangements of parts and steps.

Claims (20)

1. A system adapted to be secured substantially adjacent to a body surface of a patient to effect delivery of at least one substance across said body surface and into said patient, the system comprising: at least one aperture for receiving at least one ultrasonic transmission, said at least one substance being releasably immobilized substantially adjacent said at least one aperture; and an acoustic wave component disposed about said at least one aperture to associate said at least one transmission with said at least one substance, thereby enabling passage of said at least one substance through said body of said patient The delivery of the table. 2. The system of claim 1, further comprising at least one ultrasonic transducer adapted to be placed substantially adjacent to said hole to emit ultrasound waves transmitted through said hole, and wherein a replaceable cap contains said substance , holes and acoustic components. 3. The system of claim 2, wherein said sensor comprises a plurality of sensor elements. 4. The system of claim 2, wherein said replaceable cap further comprises a pad substantially containing said substance and disposed substantially between said aperture and the acoustic wave member. 5. The system of claim 1, wherein said acoustic wave component comprises at least one material selected from the group consisting of saran and mylar. 6. The system of claim 4, wherein said pad comprises at least one material selected from the group consisting of cotton, cellulose, and nylon. 7. The system of claim 4, further comprising a housing defining said aperture, coupled to said acoustic wave component and adapted to snap-receive said pad. 8. The system of claim 4, further comprising a semi-permeable membrane positioned substantially adjacent to said pad and forming an ultrasonically activated normally closed valve function to control said delivery of said at least one substance across said body surface of said patient. 9. The system of claim 2, wherein activation of said sensor causes said substance to pass through said acoustic wave component and collect on said surface. 10. The system of claim 2, wherein said sensor and cap are wearable on said surface. 11. The system of claim 2, wherein said system is at least partially fixed to said surface. 12. The system of claim 2, further comprising an ultrasonic sensor driver for selectively activating said sensor based on at least one dosing requirement. 13. The system of claim 2, wherein said ultrasonic transmission comprises a signal of about 20 to about 30 kHz, about 125 to about 225 mW/cm. 14. The system of claim 13, wherein said cap is releasably coupled to said sensor. 15. The system of claim 14, wherein said cap is threaded or snapped onto said sensor. 16. The system of claim 2, wherein said sensor includes a groove for facilitating securing said cap to said sensor. 17. The system of claim 2, wherein said cap further comprises an inner ring and an outer ring coupled to each other, wherein said inner ring includes a groove adapted to mate with said groove in said sensor. protrusions. 18. The system of claim 2, wherein said cap includes a pad substantially containing said substance, and said cap presses said pad against said sensor. 19. A system adapted to be secured substantially adjacent to a body surface of a patient for delivery of at least one substance across said body surface and into said patient, the system comprising: a sensor housing; a plurality of ultrasonic transmitters in the sensor housing; a cap defining at least one aperture for receiving emissions from said element; a pad that releasably secures said at least one substance substantially adjacent said at least one aperture in said cap; and an acoustic wave member positioned with respect to said at least one aperture to associate said emission with said at least one pad to effectuate delivery of said at least one substance across said body surface of said patient. 20. The system of claim 19, wherein when the cap is secured to the sensor and the system is secured to the surface, the substance is secured by the pad substantially adjacent to the surface .

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