MODIFIED TRANSDERMAL DELIVERY PATCH WITH MULTIPLE ABSORBENT PADS

Abstract

The invention is modified transdermal patch, which contains two or more absorbent pads placed atop one another within the drag reservoir of the patch, enabling the patch to (1) hold a greater quantity of the drag, (2) extend the useful life of the patch, (3) enhance the quantity of the dose which can be released from the patch, by either passive of active methods of drag release.

Claims

1-24. (canceled)

25. A method for transporting a drug through skin of an individual, comprising applying ultrasound through a transdermal delivery device which is affixed to a programmable ultrasonic regulator device, which itself is worn by the individual wherein the ultrasound is applied at a frequency and intensity and for a time period effective to enable movement of a therapeutic quantity of the drug from a transdermal delivery device, or transdermal patch, through the skin, for the purpose of effecting regulated, and timed drug delivery to the individual, wherein the wearable, portable sonic device is controllable through programmable automatic or manual operation settings comprising quantity of drug released by the device, time interval of active ultrasonic drug delivery, time interval between ultrasonic drug deliveries, frequency and intensity of the ultrasound, a basal delivery schedule of drug dosing and a bolus delivery schedule of booster doses of drug delivery.

26. The method of claim 1, wherein the ultrasound has a frequency in the range of about 20 kHz to 10 MHz. and an intensity in the range of about 0.01 W/cm.sup.2 to 5.0 W/cm, wherein the ultrasound is applied either in a continuous pulsed manner.

27. The method of claim 1, wherein the drug is insulin and the basal delivery schedule of insulin to the subject for the treatment of diabetes.

28. A method of instilling a sonic memory into materials used as a semipermeable film layer or membrane of a transdermal patch, wherein the materials are subjected to ultrasound at a reactant frequency and intensity level, while being formulated and cast into a film or membrane state, for a period of time as to make the film or membrane activate its reverse osmosis properties or pore dilation in response to an ultrasonic signal of the same amplitude, frequency and intensity level used during the formulation process.

29. A method of enhanced drug delivery employing a modified transdermal patch, wherein the modified transdermal patch comprises at least two absorbent pads or layers which are stacked upon each other, providing for increased absorption of a substance enabling the patch to (1) hold a greater quantity of the drug, (2) extend the useful life of the patch, (3) enhance the quantity of the dose which can be released from the patch, by either passive or active methods of drug release.

30. The method of claim 5, wherein the at least two stacked absorbent pads or layers are stacked without adhesive being in a path of drug delivery through the patch to avoid interaction between a drug delivered through the patch and adhesive.

31. The method of claim 5, wherein the at least two absorbent pads or layers are at least partially separatable such that an airspace can be created between at least a portion of the at least two pads or layers.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 is a diagram illustrating the design of a Reservoir Transdermal Patch.

[0056] FIG. 2 is a Drug-In-Adhesive Matrix Construction Patch.

[0057] FIG. 3 is an illustration of the structure of human skin.

[0058] FIG. 4A is an illustration of a transdermal patch incorporating an absorbent pad construction.

[0059] FIG. 4B illustrates weave patterns in absorbent material.

[0060] FIG. 4C illustrates an embodiment of a modified substance delivery device incorporating at least two absorbent layers of material within the patch

[0061] FIGS. 4D-4M illustrate views of absorbent layers may that may be stacked on top of each other.

[0062] FIG. 5A illustrates an exploded view of a transdermal patch incorporating more than one absorbent pad within the patch, stacked, in such a way to increase the holding power of the patch, the delivery rate of the drug from said patch, increase the longevity of the patch and providing for an adhesive free drug interaction.

[0063] FIG. 5B is a bottom view of a transdermal patch.

[0064] FIG. 5C is a view of a transducer assembly.

[0065] FIG. 6 is a Top View depiction of a flexible transdermal patch design modified to use the mesh screen at the bottom of the batch. This particular design uses an absorbent pad to hold the drug and the drug is liberated under an Active control fashion using ultrasound.

[0066] FIG. 7 is the Bottom View of a flexible transdermal patch design, incorporating multiple absorbent pads, illustrating the drug reservoir of the patch.

[0067] FIG. 8A is an Active transdermal delivery device termed a Patch-Cap, designed to mate with a transducer coupler for the purpose of delivering insulin, employing a double stacked absorbent pad construction, a Screen Mesh fabric at the bottom of the transdermal Patch-Cap.

[0068] FIG. 8B illustrates how an ultrasonic transducer coupler is mated to the Patch-Cap illustrated in FIG. 8A, when used with ultrasonically based drug delivery systems.

[0069] FIG. 9 is an Active transdermal delivery device which incorporates a two-part design, incorporating a transducer coupler which is slid into or snaps onto a flexible patch, fitted with multiple absorbent pads and a mesh screen for the purpose of delivering insulin.

[0070] FIG. 10 is an illustration of a Franz cell, used for collecting a liberated drug from a Transdermal Delivery Device or Patch.

[0071] FIG. 11 is an illustration of a single absorbent pad.

[0072] FIG. 12 is an illustration of a Dual or multi-absorbent pad system.

[0073] FIG. 13 is a flow chart for a method of the invention.

DESCRIPTION OF THE INVENTION

[0074] It is to be understood that the figures and descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the present invention, while eliminating, for purposes of clarity, many other elements found in conventional ultrasonic substance delivery systems. Those of ordinary skill in the art will recognize that other elements are desirable and/or required in order to implement the present invention. However, because such elements are well known in the art, and because they do not facilitate a better understanding of the present invention, a discussion of such elements is not provided herein.

[0075] As used herein, the term substance may include, but are not limited to, any substance, solution or suspension including, but not limited to, a medicinal or non-medicinal substance which may be transported through a live surface or live membrane, including, but not limited to, live tissue and other types of live membranes. The term delivery device includes transdermal patches and bandages. The term proximal means toward the end of a delivery device where the substance is released from the device. The term distal means toward the end of the device that is away from where the substance is released from the device.

[0076] Structure of Human Skin and Drug Transport Dynamics.

[0077] FIG. 3 illustrates the structure of human skin. Essentially there are three pathways through the skin into the bloodstream: [0078] 1. Breaching the Stratum Corneum. [0079] 2. Passing pharmaceutical agent through pores in the skin. [0080] 3. Passing a pharmaceutical agent through the skin by following the hair follicle to the hair root, and from there into the vascular network located at the base of the hair root.

[0081] FIG. 1 is a diagram illustrating the design of a Reservoir Transdermal Patch. Characterized by the inclusion of a liquid reservoir compartment containing a drug solution or suspension, which is separated from a release liner by a semi permeable membrane and an adhesive.

[0082] Commercial examples include: Duralgesic (Fentanyl), Estraderm @(estradiol) and Transderm-Nitro (Nitroglycerin).

[0083] A Matrix Type Patch is Similar to the Reservoir Type Patch design but has two distinguishing characteristics:

[0084] 1. The drug reservoir is provided within a semisolid formulation.

[0085] 2. There is no membrane layer. [0086] Commercial Examples include Habitol (Nicotine), Nitrodisc (Nitroglycerine and ProStep (Nicotine)

[0087] FIG. 2 is a Drug-In-Adhesive Matrix Construction Patch also known as a DIA Patch. Characterized by the inclusion of the drug directly within the skin-contacting adhesive (Wick 1988). In this design the adhesive fulfills the adhesion-to-skin function and serves as the formulation foundation, containing the drug and all the excipients. (Wilking 1994). This category also has two sub-sections: Monolithic and Multilaminate.

[0088] Commercial examples include Monolithic DIA: Climara (Estradiol), Multilaminate DIA: Nicoderm (Nicotine)

[0089] The DIA patch design has several advantages in reducing the size of the overall patch and provides a more concentric seal upon the skin. DIA patches tend to be more comfortable to wear and very thin. A typical DIA patch is 165 to 200 Um thick. Major disadvantages include a longer drug delivery profile. The release of the drug from a DIA patch follows first order kinetics, that is, it is proportional to the concentration of drug within the adhesive. As the drug is delivered from the DIA patch the drug concentration will eventually begin to fall. The delivery rate therefore falls off over time and this fact needs to be considered in the clinical evaluation phase of development.

Transdermal Delivery Device Incorporating an Absorbent Pad Construction

[0090] FIG. 4 is a schematic drawing of a transdermal patch incorporating an absorbent pad construction. In some embodiments, the Patch or Transdermal delivery Device (4.1) can include a backbone material (4.1) which holds the materials together, which is comprised itself of a top portion membrane film (4.2), which in this illustration is designed to be used with ultrasound and is termed a sonic membrane (4.2). At the bottom of the patch (4.1) is a Semi-permeable film (4.4) and a Peel Away film (4.5).

[0091] Within the patch interior a substance (4.11) is absorbed onto an absorbent pad (4.3), and contained within the drug reservoir compartment (4.8). In an Active Patch embodiment, ultrasound (4.6), or another energy medium, may be delivered through the top membrane (4.2) through the patch (4.1), and will have the effect of liberating the substance (4.9) from the patch (4.) onto the skin's surface (4.10). In this embodiment the substance (4.11) is absorbed and stored within the absorbent pad (4.3) which can hold the drug, free of adhesive interaction for lengthy periods of time depending upon the thickness of the absorbent pad, and its holding power.

[0092] Once the substance (4.11) is liberated from the absorbent material (4.3) it travels to the proximal end 50, which may be the bottom, of the patch (4.1) and in some embodiments, through a separator, which can be, but is not limited to, a semi-permeable film layer (4.4) or mesh screen. The proximal end 50 of the patch is the end of the patch toward where the substance is released from the patch. The distal end 52 of the patch is the end of the patch that is generally away from the end were the substance is released from the patch. The semi-permeable film layer (4.4) can be comprised of a film with micro-pores or a mesh screen which will disperse the liberated substance onto droplets (4.9) which then fall onto the skin's surface and are absorbed. In some embodiments, to prepare the patch for use a peel away film 4.5 is peeled away from the bottom of the patch. Once the peel away film (4.5) is removed the flow of the stored drug can be effected in a Passive patch or when an energy media such as ultrasound (4.6) is applied to the Active patch.

[0093] Several materials may be used as an absorbent. One preferred material is a cellulose based composition. Common materials such as cellulose, cotton, fabrics, and synthetic fibers such as nylon or sponges may be employed to absorb the medicant, drug or substance. Additionally the weave pattern is a factor in determining the quantity of the drug which can be stored. FIG. 4B is an exemplary illustration of the several weave patterns, known in the art, which may be used in absorbent materials. It is possible to store as much as 100 times the weight of the absorbent material in moisture. Typically a cellulose pad, 1 millimeter thickness and sized 1 inch in diameter will have an absorbency power of 3 X, 3 times its weight in water. Increasing the thickness of the pad, or changing the weave pattern can increase the absorbency power. By choosing the right absorbent material, and adjusting its thickness, a higher absorbency power can be achieved, and therefore a higher dose of the drug can be deposited onto the patch.

[0094] A transdermal Patch using the construction illustrated in FIGS. 4A and 4B, and covered by U.S. Pat. No. 7,440,798, Substance Delivery Device, Bruce K. Redding, Jr. inventor, granted Oct. 21, 2008, showed that the delivery of Insulin via ultrasound was very effective using the absorbent pad construct. The pad liberated the insulin in response to an active ultrasonic transmission and when no ultrasound was present the semi-permeable film ceased the delivery of the drug.

[0095] However a problem ensued with the patch developed according to FIG. 4B, in that the drug loaded upon the patch tended to deliver up to 50% of the load and not a higher delivery rate. The weave pattern, as exemplarily shown on FIG. 4B, determines the hold capacity for the drug and its eventual release rate under ultrasonic propagation. As the drug was pushed from the absorbent material the residual holding power of the absorbent increased. While this patch avoided the interaction between the drug and the adhesive common in the patch constructs indicated in FIG. 1 and FIG. 2, it was often incapable of long term delivery options as too much of the drug load was retained in the absorbent.

[0096] Increasing the thickness of the absorbent pad did not solve this problem. While more drug could be stored with a thicker pad, the result was often that the delivery rate was excessive and once again only 50% of the load could be liberated.

[0097] One solution was simply to use multiple thin absorbent at least partially separatable layers, stacked on top of each other. One solution was simply to use multiple thin absorbent pads, stacked on top of each other.

Delivery Device Including at Least a Double Absorbent Layer

[0098] According to embodiments of the present invention, a delivery device is provided for enhancing substance delivery by the use of ultrasound. Use of ultrasonics is particularly effective in delivering larger pharmaceutically active compounds, wherein the delivery device is made to accommodate both the special needs of ultrasonic excitation through the patch construct and the delivery of medicinal compounds stored within the patch.

[0099] It is to be understood that in some embodiments the delivery devices can include transdermal delivery of substances and in some embodiments can include the delivery of substances directly on other types of living tissues and membranes. Delivery devices include transdermal patches and bandages.

[0100] Reference is now made to FIGS. 4C-4M. FIG. 4C illustrates embodiments of a modified substance delivery device incorporating at least two absorbent layers of material within the patch, wherein the at least two absorbent layers 54 are stacked on top of each other and are at least partially separatable such that a small airspace 56 can be created between at least a portion of the at least two layers. In some embodiments, the at least two layers are stacked in a manner in relationship to each other such that the flow of the absorbed substance is generally perpendicular to the stacked layers or such that the flow of the absorbed substance 4.9 from the absorbent layers to exit the patch requires the substance from the layer or layers distal 52 to the exit area of the device to flow through the layer or layers proximal 50 to the exit area of the device before exiting the patch. In some embodiments, the at least two layers are stacked in a manner in relationship to each other such that the flow of the absorbed substance is generally perpendicular to the stacked layers and such that the flow of the absorbed substance from the absorbent layers to exit the patch requires the substance from the layer or layers distal 52 to the exit area of the device to flow through the layer or layers proximal 50 to the exit are of the device before exiting the device.

[0101] As exemplarily illustrated in FIGS. 4D-4E two or more layers 54 may be stacked on top of each other. It is to be understood that the shape of the absorbent material may be in any variety of shapes. FIG. 5A exemplarily illustrates the absorbent material in the shape of separate circular pads 28. However, it would also be possible to create the stacking with other manners and mechanisms. FIGS. 4F-4M are non-exhaustive exemplary illustrations of other ways that the layers of absorbent material stacking could be accomplished in a transdermal delivery device.

[0102] FIGS. 4F-FH and L exemplarily illustrate that at least on piece of absorbent material can be folded over to created the stacked layers. The absorbent material could be folded over once of more than once to create at least two layers, and an increasing number of layers upon additional folding of the material. FIG. 4L illustrates that an absorbent material could be folded two times to create three absorbent layers, and it is to be understood that the invention includes folding an absorbent material additional times to create addition layers, such as but not limited to folding the material three times to create four layers, folding it four times to create five layers, and making additional folds to create additional layers. FIGS. 4I-FJ exemplarily illustrate that that at least one of absorbent material that can be folded over to created the staked layers could have a portion of thinner material 58 at the place where the fold will or does occur, which would remove some of the bulk at the place of the fold.

[0103] FIG. 4F-M exemplarily illustrates that a piece of absorbent material could be shaped in a variety of different shapes, including but not limited to a general circular shaped when folded. In addition, there could be a cut-out area 60 between the layers to create the shape and to reduce the material that would be required to be folded.

[0104] Reference is now made to FIG. 5A. In this exemplary embodiment, the patch includes a Cap (20) into which an array of transducer discs (21) are placed. A foam ring (22) is affixed to the stainless steel face plate (23) on one end and to the Cap (20) to provide a cushion. The transducer discs (21) are sealed against moisture or air contact within the Cap enclosure 20). The Transducer Cap (20) is thereby removable and can be connected or detached from the transdermal patch (24).

[0105] The patch (24) is comprised of a backbone layer of plastic ideally shaped in the form of a butterfly but can be any other shape, An adhesive tape section (25) is cut to the shape of the backbone (24) and comes into contact with the patients skin, but is not in the path of any drug contained with the patch (24).

[0106] A membrane film (26) is placed across the backbone layer (32) and acts to protect any stored drug. In the case of an ultrasonic patch the membrane film (26) enables ultrasound to pass through the film without deflection.

[0107] Next at least two absorbent pads, (28) are stacked on top of one another.

[0108] At the bottom of the patch (24) a mesh screen (29) is placed and this is then covered over with a Rate Control Film (30).

[0109] One embodiment is a butterfly patch design, with a snap in ultrasonic transducer when used for a substance delivery system, which in some embodiments could be an insulin delivery system, powered by ultrasound. This is shown in the photograph in FIG. 5B.

[0110] FIG. 5C Shows the design of a Transducer Coupler, which is comprised of a stainless steel face plate (23) onto which one or more, four showing, transducer discs are placed. The transducers disc (21) may be a magneto restrictive or piezoelectric transducer crystal, which will convert an electric signal into mechanical forces, sufficient top drive a drug stored on the absorbent pads (28) from the confines of storage within the patch (24), liberated from the patch and onto the surface of the skin of the patient.

[0111] While an active patch, powered by ultrasound is shown in FIG. 5A, it should be apparent that this invention can be utilized with other energy transmissions besides ultrasound including radio frequency, light, laser and heat therapy transmission devices.

[0112] While an active patch, powered by ultrasound is shown in FIG. 5A, it should be apparent that this invention can be utilized in a passive delivery application as well and is not limited to active delivery systems,

Transdermal Delivery Device Incorporating an Alternative Flexible Patch Design with Snap-Connector to a Transducer Coupler Capability

[0113] FIG. 6 is a Top View depiction of a flexible transdermal patch design modified to use the mesh screen at the bottom of the batch. This particular design uses two absorbent pads to hold the drug and the drug is liberated under an Active control fashion using ultrasound. In this design the flexible patch may be used passively with low molecular weight drugs, generally below 1,000 Daltons. On the top of the patch (6.1) is a snap (6.3) which can attach the patch (6.1) to an ultrasonic transducer device, which in turn sends an ultrasonic transmission through the patch and liberates the drug stored within the absorbent pad section (6.2) onto the surface of the skin.

[0114] In FIG. 7, the rear side of the flexible patch is shown. The backbone (7.1) or border of the patch which comes into contact with the skin has an adhesive border (7.4) to stick the patch to the skin's surface. The adhesive (7.4) does not come into contact with the drug directly. The absorbent pad or stacked pads (7.2) is placed within a bordered well or reservoir section (7.5) which isolates it from contact with the adhesive layer (7.4) through the use of a gasket (7.6). At the very bottom of the patch a mesh screen (7.7) is placed across the drug reservoir (7.5) and over the absorbent pad or collection of stacked absorbent pads (7.2). Using this construction a transdermal patch forms minute droplets of the drug upon the skin's surface as depicted in FIG. 4, either through passive or active means. This design patch is especially suited for ultrasonic drug delivery.

Patch-Cap Design Transdermal Delivery Device

[0115] FIG. 8A is an Active transdermal delivery device termed a Patch-Cap, designed to mate with a transducer coupler for the purpose of delivering insulin, employing a Screen Mesh fabric at the bottom of the transdermal Patch-Cap.

[0116] FIG. 8B illustrates how the Transducer coupler is mated to the Patch-Cap illustrated in FIG. 8A.

[0117] FIG. 8A is an illustration of a Transdermal Patch Cap designed to deliver insulin transdermally using ultrasonic propagation. The Patch Cap includes two absorbent pads (14), which are placed one top of the other (one is shown in the drawing) and which are placed within a holder, the outer snap ring (8.30). It is to be understood that the Transdermal Patch Cap could also be used with one absorbent pad 14. In addition, in some embodiments more than two absorbent pads 14 could be included. In addition, in some embodiments, on absorbent material could be formed into more than one layer of absorbent substance as exemplarily illustrated in FIGS. 4F-M. It is locked into place by an inner snap ring (8.20) and then is used to absorb a substance. This device can be used for insulin delivery. The Cap (8.9) has threaded sides (8.12) in one embodiment and a cap connector grove (8.11) which fits into an ultrasonic emission transducer coupler (8.40). The mesh screen (8.5) is placed across the absorbent pad (8.14) at the bottom of the patch cap. Using this construction a transdermal patch-cap forms minute droplets of the drug upon the skin's surface as depicted in FIG. 4B, either through passive or active means. This design patch is especially suited for ultrasonic drug delivery.

[0118] FIG. 8B illustrates how an ultrasonic transducer coupler is mated to the Patch-Cap illustrated in FIG. 8A, when used with ultrasonically based drug delivery systems.

Active Transdermal Delivery Device which Incorporates a Two-Part Design, Incorporating a Transducer Coupler which is Slid into or Snaps onto a Flexible Patch

[0119] FIG. 9 is an Active transdermal delivery device which incorporates a two-part design, incorporating a transducer coupler which is slid into or snaps onto a flexible patch, fitted with multiple absorbent pads and a mesh screen for the purpose of delivering insulin.

[0120] A Backbone layer (9.1) is the base of the patch. A transducer assembly (9.3) snaps onto the patch (9.1) at the top of the patch by connecting to the well cap (9.2) Directly at the top of the patch a film which may allow ultrasound to penetrate it (9.6) is placed directly above the Absorbent Well (9.5), which contains at least two absorbent pads, on top of the other, into which a dose of a particular substance or drug may be stored. In the initial application of this design insulin is stored within each absorbent pad so that the patch may be used to treat diabetes. In addition, in some embodiments more than two absorbent pads 14 could be included. In addition, in some embodiments, on absorbent material could be formed into more than one layer of absorbent substance as exemplarily illustrated in FIGS. 4F-M. A sealing gasket (9.4) can be placed around the well (9.5) to isolate it from any adhesive used in the border of the patch (9.1). A mesh screen (9.7) is installed at the bottom of the patch ahead of a peel away film (9.8) It is to be understood that in some embodiments of this device, the mesh screen and/or the peel away film could be omitted.

[0121] Referring now to FIG. 13, a flow chart for a method of the invention is illustrated. Embodiments of the method of the invention include, but are not limited to, utilization of the devices, dimensions, function, design and materials described in the device embodiments of the invention. In one embodiment, the method includes providing 70 a substance delivery device, providing 72 at least two layers of an absorbent material on to which a substance has been absorbed, placing 74 the device adjacent to a living tissue or next to a material through which the substance my flow to access living tissue, and allowing 76 the release of the substance to access the living tissue.

EXPERIMENTS

Comparison of Patch-Capsutilizing a Single Absorbent Pad Vs. A Double Absorbent Pad Construction, Delivery of Insulin when Propagated by Ultrasound, Using the Patch-Cap Construction Indicated In FIGS. 8A and B

Experiment 1

Experiment Number: BKR-1011-001

[0122] FIG. 10 is an illustration of a Franz cell, used for collecting a liberated drug from a Transdermal Delivery Device or Patch. In FIG. 10 Ultrasound (10.1) is delivered from a transducer (10.2) to a patch (10.3) mounted on a flask (10.5). A sample of human skin (10.4) can be placed under the patch (10.3). Ultrasound traveling through the patch will liberate drugs stored within the patch, which will then flow through the skin section and into the receiver compartment of the flask (10.5). There a magnetic stir bar (10.6) is used to circulate the liberated drug in the receiver compartment (10.5). Samples of the liberated drug may be taken from the receiver compartment (10.5) via the sampling port (10.7). A clamp (10.8) is used to hold the Patch onto the Franz cell.

[0123] In this experiment an absorbent system was compared, one using a single absorbent pad and one using a stacked absorbent pad. FIG. 11 is an illustration of a single absorbent pad system. FIG. 12 is an illustration of a Dual or multi-absorbent pad system. In this experiment an absorbent pad was fabricated according to the following dimensions:

Patch Cap Specifications:

[0124] Composition:

TABLE-US-00001 Polyvinylidene Chloride Saran Film Absorbent Material Protective Backing (To be specified)

[0125] Sandwiched pad comprising of a top section comprised of Saran Polyvinylidene Chloride film, followed by a mid-section absorbent material comprised of 100% virgin wood pulp cellulose fiber supplied by Buckeye Products Co, and a synthetic emulsion binder and an under section which includes a of protective film.

Sonic Membrane Specifications:

[0126] Manufacturer: SC Johnson [0127] Brand Name: Saran Classic [0128] Chemical Name: Polyvinylidene Chloride [0129] Thickness: 0.5 mil

Absorbent Material Physical Properties: BKR-1011-3

[0130] Pad Material: Woven cellulose fiber, un-bleached
Pad Diameter: 2.25 inch

Pad Thickness: 0.92 mm Thickness

[0131]

TABLE-US-00002 Basis Weight 70 g/m2 MQ3RD001 Estimated Slit Thickness 0.92 mm/ply MQ3RD002 MD Dry Tensile 750 g/25.4 mm MQ3RD003 CD Dry Tensile 635 g/25.4 mm MQ2RD003 CD Wet Tensile 310 g/25.4 mm MQ3RD004 Absorbency Rate 3.0 seconds (water) MQ3RD005 Absorbency Capacity 12.0 g/g (water) MQ3RD005 Brightness 81% MQ3RD007
Holding Capacity: 100 units insulin [0132] (Humalog R supplied by the Lilly Company) [0133] (100 units/cc)

[0134] In Experiment 1 a Patch-Cap is configures according to FIG. 8A using a single absorbent wafer as shown in FIG. 11. 100 units of Humalog insulin is loaded onto the absorbent pad and the Patch cap configured onto a test Franz cell, as shown in FIG. 10, with no human skin utilized in this experiment. The transducer array was a 4 transducer coupler as shown in FIG. 5C, being model Number Piezoelectric Transducer Standard Array for U-Strip UTDD, Model No: EX1-4 manufactured by Transdermal Specialties Co., and powered by an ultrasonic driver device manufactured by Transdermal Specialties Co. and known as U-STRIP DESKTOP ULTRASONIC DRIVER, Model No. ESI-25.

[0135] The Patch-Cap, single absorbent pad is loaded with 100 units of Lispro insulin (Humalog R-100 supplied by Eli Lilly Co.) and is powered by an ultrasonic applicator for a total of 8 hours.

Ultrasonic Settings & Single Absorbent Pad

[0136]

TABLE-US-00003 Ultrasonic Frequency: 23 kHz Intensity: 500 mW/sq. cm Ultrasonic Transmission Alternating between 50 milliseconds saw tooth and 50 milliseconds square wave form. This alternation avoid cavitation or over heating of the insulin within the Patch-Cap. Dimensions of Patch-Cap 2.25 inch diameter absorbent pad area Absorbent pad used BKR-1011-003 Cellulose, 1 mil thickness Number of absorbent One pads in Patch-Cap Duration of Experiment: 8 hours under continuous ultrasound Filter Screen used 100 100 mesh on bottom of Patch- cap

[0137] The delivery pattern of the drug upon the surface of the skin corresponded to the pooling effect shown in FIG. 4B.

Results:

[0138]

TABLE-US-00004 Duration of Ultrasonic exposure 8 hours total First 4 hours Delivery Rate (Insulin 7.2 units of insulin per hour collected from Franz Cell) for a total of 28.8 units collected at hour 4 Second 4 hour Period Delivery Rate 4.3 units of insulin per hour (Insulin collected from Franz Cell) for a Total of 17.2 units collected between Hour 4 and at hour 8 Total cumulative amount of insulin 46 units collected after 8 hours Balance of insulin remaining in 54 units absorbent pad system(single pad) Third 4 hour period Delivery Rate 1.2 units of insulin per hour (Insulin collected from Franz Cell) for a total of 4.8 units collected between hour 8 and at hour 12 Total accumulated amount of insulin 50.8 units collected after 12 hours Balance of insulin remaining in 49.2 units. absorbent pad system(single pad) Note: no quantity of insulin could be liberated after hour 12.

[0139] Using a single absorbent pad construction, after 8 hours of ultrasonic driving power, the patch-Cap could release only 50.8% of the load of insulin upon the absorbent pad.

[0140] For a 200 lb. man, with a maximum need of 3.8 units of Lispro insulin per hour the single absorbent patch-cap could only be relied to work for 12 hours or to deliver a maximum of 46 units before the delivery rate from the patch would fall below the listed need for the average 200 lb. male diabetic.

Experiment 2

Experiment Number: BKR-1011-002

[0141] In Experiment 2 a Patch-Cap is configures according to FIG. 8A using a single absorbent pad, at 2 mm thickness. 100 units of Humalog insulin is loaded onto the absorbent pad and the Patch cap configured onto a test Franz cell, as shown in FIG. 10, with no human skin utilized in this experiment. The transducer array was a 4 transducer coupler as shown in FIG. 5C, being model Number Piezoelectric Transducer Standard Array for U-Strip UTDD, Model No: EX1-4 manufactured by Transdermal Specialties Co., and powered by an ultrasonic driver device manufactured by Transdermal Specialties Co. and known as U-STRIP DESKTOP ULTRASONIC DRIVER, Model No. ESI-25.

[0142] The Patch-Cap, a thicker, single absorbent pad, at 2 mm thickness, is loaded with 100 units of Lispro insulin (Humalog R-100 supplied by Eli Lilly Co.) and is powered by an ultrasonic applicator for a total of 8 hours.

Ultrasonic Settings & Double Absorbent Pad

[0143]

TABLE-US-00005 Ultrasonic Frequency: 23 kHz Intensity: 500 mW/sq. cm Ultrasonic Transmission Alternating between 50 milliseconds saw tooth and 50 milliseconds square wave form. This alternation avoid cavitation or over heating of the insulin within the Patch-Cap. Dimensions of Patch-Cap 2.25 inch diameter absorbent pad area Absorbent pad used A single BKR-1011-003 Cellulose, 2.0 mil thickness Number of absorbent One pads in Patch-Cap Duration of Experiment: 8 hours under continuous ultrasound Filter Screen used 100 100 mesh on bottom of Patch- cap

[0144] The delivery pattern of the drug upon the surface of the skin corresponded to the pooling effect shown in FIG. 4B.

Results:

[0145]

TABLE-US-00006 Duration of Ultrasonic exposure 8 hours total First 4 hours Delivery Rate (Insulin 7.2 units of insulin per hour collected from Franz Cell) for a total of 28.8 units collected at hour 4 Second 4 hour Period Delivery Rate 5.8 units of insulin per hour (Insulin collected from Franz Cell) for a Total of 23.2 units collected between Hour 4 and at hour 8 Total cumulative amount of insulin 52.0 units collected after 8 hours Balance of insulin remaining in 48 units absorbent pad system(single pad) Third 4 hour period Delivery Rate 4.6 units of insulin per hour (Insulin collected from Franz Cell) for a total of 18.4 units collected between hour 8 and at hour 12 Total accumulated amount of insulin 70.4 units collected after 12 hours Balance of insulin remaining in 29.6 units. absorbent pad system(single pad) Note: no quantity of insulin could be liberated after hour 12.

Experiment 3

Experiment Number: BKR-1011-002

[0146] In Experiment 2 a Patch-Cap is configures according to FIG. 8A using a double absorbent wafer as shown in FIG. 12A. 100 units of Humalog insulin is loaded onto the absorbent pad and the Patch cap configured onto a test Franz cell, as shown in FIG. 10, with no human skin utilized in this experiment. The transducer array was a 4 transducer coupler as shown in FIG. 5C, being model Number Piezoelectric Transducer Standard Array for U-Strip UTDD, Model No: EX1-4 manufactured by Transdermal Specialties Co., and powered by an ultrasonic driver device manufactured by Transdermal Specialties Co. and known as U-STRIP DESKTOP ULTRASONIC DRIVER, Model No. ESI-25.

[0147] The Patch-Cap, single absorbent pad is loaded with 100 units of Lispro insulin (Humalog R-100 supplied by Eli Lilly Co.) and is powered by an ultrasonic applicator for a total of 8 hours.

Ultrasonic Settings & Double Absorbent Pad

[0148]

TABLE-US-00007 Ultrasonic Frequency: 23 kHz Intensity: 500 mW/sq. cm Ultrasonic Transmission Alternating between 50 milliseconds saw tooth and 50 milliseconds square wave form. This alternation avoid cavitation or over heating of the insulin within the Patch-Cap. Dimensions of Patch-Cap 2.25 inch diameter absorbent pad area Absorbent pad used BKR-1011-003 Cellulose, 1 mil thickness 2, STACKED ON TOP OF ONE ANOTHER Number of absorbent Two pads in Patch-Cap Duration of Experiment: 8 hours under continuous ultrasound Filter Screen used 100 100 mesh on bottom of Patch- cap

[0149] The delivery pattern of the drug upon the surface of the skin corresponded to the pooling effect shown in FIG. 4B.

Results:

[0150]

TABLE-US-00008 Duration of Ultrasonic exposure 12 hours total First 4 hours Delivery Rate (Insulin 16.4 units of insulin per hour collected from Franz Cell) for a total of 65.6 units collected at hour 4 Second 4 hour Period Delivery Rate 15.8 units of insulin per hour (Insulin collected from Franz Cell) for a Total of 63.2 units collected between Hour 4 and at hour 8 Total cumulative amount of insulin 128.8 units collected after 8 hours Balance of insulin remaining in 71.2 units absorbent pad system(single pad) Third 4 hour period Delivery Rate 14.6 units of insulin per hour (Insulin collected from Franz Cell) for a total of 58.4units collected between hour 8 and at hour 12 Total accumulated amount of insulin 187.2 units collected after 12 hours Balance of insulin remaining in 12.8 units. absorbent pad system(single pad) Note: no quantity of insulin could be liberated after hour 12.

COMPARISON and OBSERVATIONS

[0151] Using a double absorbent pad construction, under continuous ultrasonic driving power, the Patch-Cap could release over twice the load of insulin to a diabetic patient.

[0152] For a 200 lbs. man, with a maximum need of 3.8 units of Lispro insulin per hour the single absorbent patch-cap could only be relied to work for 12 hours or to deliver a maximum of 46 units before the delivery rate from the patch would fall below the listed need for the average 200 lb. male diabetic.

[0153] The use of a thicker pad was not as effective as a double pad use, stacked on top of one another.

[0154] For a 200 lbs. man, with a maximum need of 3.8 units of Lispro insulin per hour the double absorbent patch-cap could be relied to work for 49 hours or to deliver a maximum of 187 units before the delivery rate from the patch would fall below the listed need for the average 200 lb. male diabetic.

[0155] The use of a double absorbent pad extended the useful delivery capability of the ultrasonically powered insulin patch by a factor of 4.

[0156] In fact, coupled with an ultrasonic propagation mechanism this experiment demonstrated significant advantages to the treatment of diabetes, through the use of a transdermal delivery device which is constructed with multiple absorbent pads instead of using one pad or even a pad with a greater overall thickness.

[0157] Combination Ultrasonic Device and Transdermal Patch:

[0158] The invention further includes a method for conducting the transport of active substances, including but not limited to pharmaceutical compositions, through the body surface of an individual. The method includes applying ultrasound through a transdermal delivery device which is attached with to a programmable ultrasonic regulator device, which itself is worn by the individual wherein said ultrasound is applied at a frequency and intensity and for a time period effective to enable movement of a therapeutic quantity of the active pharmaceutical composition from a transdermal delivery device, or transdermal patch, through the skin, for the purpose of effecting regulated, and timed drug delivery to the individual.

[0159] The method of can also include providing an ultrasound having a frequency in the range of about 20 kHz to 10 MHz, and having intensity in the range of about 0.01 W/cm.Math.sup.2 to 5.0 W/cm.Math.sup.2, and wherein the ultrasound is applied either in a continuous or pulsed manner.

[0160] The method can further include affixing or connecting the wearable, portable sonic device with a transdermal patch which provides the transdermal delivery of drugs or other substances to the individual. The connection can be effected via the use of a snap-on feature built into the transdermal patch, or by some other effective connector which provides a connection of the backbone of the patch with a transducer or array of transducers.

[0161] The method can further include providing that the wearable, portable sonic device is controllable through programmable settings for at least one of the following: the quantity of drug released by the device, the time interval of active ultrasonic drug delivery, the time interval between ultrasonic drug delivery, the frequency and intensity of the ultrasonic signal, the basal delivery schedule of drug dosing and the bolus delivery schedule of booster doses of a particular drug, with both automatic functions and a manual operation capability.

[0162] The invention further includes a delivery device for conducting the transport of active substances, including but not limited to pharmaceutical compositions, through the body surface of an individual, which is attachable with a programmable ultrasonic regulator device. The programmable ultrasonic regulator device is wearable by the individual wherein ultrasound is applied through the device at a frequency and intensity and for a time period effective to enable movement of a therapeutic quantity of the active pharmaceutical composition from a transdermal delivery device, or transdermal patch, through the skin or live tissue for the purpose of effecting regulated, and timed drug delivery to the individual. The delivery device can also contain a transducer assembly, holding a single or multiple transducers of any effective type including cymbal type, wherein the transducer assembly may be internal or external to the device.

[0163] The invention further includes an ultrasonic drug deliverer that uses a single transducer or an array of transducers, employed to deliver ultrasonic energy through a transdermal patch, wherein the array makes possible the application of the ultrasonic drug transport through a number of multiple skin transport sites. The drug deliverer avoids premature damage to the skin transport sites and effects the greatest quantity of deliverable drug from the patch, through the patients skin and into the bloodstream. In some embodiments, the multiple transducer elements in the drug deliverer transmit ultrasound at identical frequencies and intensity levels to each other. In some embodiments, the multiple transducer elements in the drug deliverer transmit ultrasound at differing frequencies and intensity levels to each other.

[0164] The invention includes an ultrasonic substance delivery transdermal patch, wherein the modified transdermal patch includes:

[0165] A) Patch Backbone and Sonic membrane: [0166] A backbone of the patch has a section including a membrane which will enable the effective transmission of the ultrasonic signal throughout the patch, said membrane possessing properties which will not interfere with the frequency or reduce the intensity of the ultrasonic transmission, wherein the membrane may be made of a material including saran, or such other polymeric compound which will similarly not interfere with the frequency and intensity of an ultrasonic transmission.

[0167] B) Absorbent Pad: [0168] An absorbent compound as a means for storing a substance, including but not limited to a medication, drug or nutrient compound within the patch, wherein an ultrasonic transmission through the patch acts to liberate the substance from the absorbent pad to be transported to the patient through skin permeation.

[0169] C) Semi-Permeable Film [0170] A semi-permeable film at the bottom of the patch, at the interface where the patch comes into contact with the patients skin. The semi-permeable film provides a means for delivering a stored substance including but not limited to a medication, drug or nutrient compound from within the patch to the patients skin surface only upon the active generation of ultrasonic transmissions through the patch thereby providing an On-Off function with the propagation of ultrasound through the patch, and a means of regulating the quantity of the substance or dose to the patient, i.e., the control of the delivered dose to the patient, wherein said semi-permeable film is comprised of a material which provides osmotic by-pass, via ultrasonic propagation, or is comprised of a membrane or film possessing perforations which expand in the presence of ultrasound and which contract when ultrasound is terminated, to enable substance delivery.

[0171] D) Gasket for providing a good seal to the skin [0172] A gasket around the backbone of the patch, as means of preventing air from reaching under the patch and interfering with the intensity of the ultrasonic transmission through the patient's skin and for preventing leakage of the drug contained within the patch.

[0173] In some embodiments of the transdermal patch, the semi-permeable film may be comprised of materials including but not limited to the following materials:

[0174] Membranes: [0175] CTA (Cellulose Tri-Acetate) [0176] TFC (Thin Film Composite) sometimes labeled as TFM (Thin Film Membrane).

[0177] Reverse Osmosis membranes made from semi permeable material such as: [0178] Cellulose tri Acetate [0179] Composite polyamide

[0180] Membrane films using; [0181] Pierced membranes [0182] Spiral wound membranes

[0183] Commercial examples of semi-permeable films include: [0184] Hytrel [0185] Surlyn [0186] Crastin [0187] Imron [0188] CA (cellulose acetate)

[0189] The at least one absorbent pad in the transdermal patch may include materials including, but is not limited to, the following list of materials:

TABLE-US-00009 Cellulose Fiber Pad Cotton Natural Sponge Woven Cloth Fabrics Polyurethane foams Polyisocynurate Foams Non-Woven Cloths Fumed Silica Starch Corn Meal Wood Pulp fibers Collagen Pads Poly methyl methacrylate Polyvinyl alcohol Poly vinyl pyrrolidine Poly acrylic acid Poly (2-hydroxy ethyl methacrylate Polyacrylamide Poly ethylene glycol Polylactides(PLA) Polyglycolides(PGA) Nylon Poly(lactide-Co-glycolides) Polypropolene Polycarbonate Chitosan Poly (N-isopropylacrylamide)
Co-Polymer formulations of Poly methacrylic acid and Poly ethylene glycol Co-Polymer formulations of Poly acrylic acid and Poly (N-isopropylacrylamide) Hyrdogels, e.g. Polyacrylamide, poly(propylene oxide Pluronic polyols family of gel materials, e.g. Pluronic-chitosan hydrogels Silica gels

[0190] It is to be understood that the at least on pad could also be made of any other natural or synthetic material, which will act to absorb the drug compound and be able to release the drug upon ultrasonic excitation.

[0191] In some embodiments, the use of an absorbent pad is made to provide extended delivery of the substance via the manipulation of the thickness of the absorbent material, or through the selection of materials with increased absorbency power, thereby enabling the absorbent pad to hold and reserve greater quantities or doses of the substance to be delivered, for a longer period of time.

[0192] In some embodiments of the invention, the delivery rate of a substance from the transdermal patch can be adjusted due to the use of an absorbent pad via the manipulation of the thickness of the absorbent material, or through the selection of materials with increased or decreased absorbency power, thereby enabling the absorbent pad to liberate the substance at differing delivery rates form the patch.

[0193] In some embodiments of the transdermal patch the use of an absorbent pad provides enhanced resistance to incidental contact between the stored substance and other materials or compounds within the patch construction which could contaminate or degrade the substance, including adhesives used in the fabrication of the patch or to adhere the patch to the patients skin surface.

[0194] In some embodiments, the invention further includes, a means of providing regulated and controlled doses of insulin and other medications for the treatment of diabetes, involving a wearable ultrasonic transmitter which is connected to a transdermal patch wherein the patch has been loaded with insulin or other medication for the treatment of diabetes. The combination device acts to regulate the dose delivered to a diabetic patient for the purpose of reducing and controlling serum glucose levels in the diabetic patient.

[0195] In some embodiments, the invention includes a combination system that includes a wearable ultrasonic transmitter which is connected to a transdermal patch for the purpose of providing regulated and controlled doses of insulin and other medications for the treatment of diabetes, wherein the insulin loaded patch is used either in conjunction with or in replacement of oral diabetic medication, for night time use, daytime use or both, for the purpose of reducing and controlling serum glucose levels in a diabetic patient.

[0196] The invention further includes an enhanced ultrasonic drug delivery transdermal patch suitable for ultrasonic drug delivery, containing an absorbent compound as a means for storing a substance, including but not limited to medication, drugs or nutrient compounds within the patch, wherein the absorbent compound is made to be more resonance compatible with the frequency and intensity of the ultrasonic transmission by pre-treating the absorbent compound to improve its sonic attenuation properties by reducing the quantity of air or gas trapped within the absorbent by: Freezing the absorbent material, and Vacuum drying the absorbent material and/or by Pre-treating the material with sonic energy to remove any impurities within the absorbent material, prior to the application of the substance to the material.

[0197] The invention further includes embodiments of a means of instilling a sonic memory into materials used as the semi-permeable film layer of a transdermal patch, wherein the materials are subjected to ultrasound at the desired reactant frequency and intensity levels, while being formulated and cast into a film or membrane state, for a period of time as to make that film or membrane activate its reverse osmosis properties or pore dilation in response to a ultrasonic signal of the same amplitude, frequency and intensity level used during the formulation process.

[0198] The invention further includes a modified transdermal delivery device which incorporates a mesh screen at the bottom of the transdermal delivery device, which contacts to the skin, for the purpose of avoiding drug pooling, improving drug absorption, and the speed of absorption of the drug.

[0199] The invention further includes a flexible transdermal patch delivery device which incorporates a mesh screen at the bottom of the transdermal delivery device, which contacts the skin, for the purpose of avoiding drug pooling, improving drug absorption, and increasing the speed of absorption of the drug.

[0200] The invention further includes embodiments of a transdermal delivery cap or patch-cap delivery device which incorporates a mesh screen at the bottom of the device, which contacts the skin, for the purpose of avoiding drug pooling, improving drug absorption, and increasing the speed of absorption of the drug.

[0201] The invention further includes a drug delivery device employing a modified transdermal patch, wherein the modified transdermal patch includes one or more absorbent pads for absorbing a substance, wherein the absorbent material is suitable as a means for storing a substance, including but not limited to a medication, drug or nutrient compound within the patch,

[0202] The invention further includes a drug delivery device employing a modified transdermal patch, wherein the modified transdermal patch includes at least two absorbent pads which are stacked upon each other. This embodiment can provide for increased absorption of a substance enabling the patch to (1) hold a greater quantity of the drug, (2) extend the useful life of the patch, (3) Enhance the quantity of the dose which can be released from the patch, by either passive of active methods of drug release.

[0203] The invention further includes embodiments of a drug delivery device employing a modified transdermal patch, wherein the modified transdermal patch includes at least one absorbent pad which has a greater thickness to the absorbent material, providing for increased absorption of a substance and enabling the patch to (1) hold a greater quantity of the drug, (2) extend the useful life of the patch, (3) enhance the quantity of the dose which can be released from the patch, by either passive of active methods of drug release.

[0204] The absorbent pads in the embodiments of the invention may include material including, but are not limited to, the following materials:

TABLE-US-00010 Cellulose Fiber Pad Cotton Natural Sponge Woven Cloth Fabrics Polyurethane foams Polyisocynurate Foams Non-Woven Cloths Fumed Silica Starch Corn Meal Wood Pulp fibers Collagen Pads Poly methyl methacrylate Polyvinyl alcohol Poly vinyl pyrrolidine Poly acrylic acid Poly (2-hydroxy ethyl methacrylate Polyacrylamide Poly ethylene glycol Polylactides(PLA) Polyglycolides(PGA) Nylon Poly(lactide-Co-glycolides) Polypropolene Polycarbonate Chitosan Poly (N-isopropylacrylamide)
Co-Polymer formulations of Poly methacrylic acid and Poly ethylene glycol Co-Polymer formulations of Poly acrylic acid and Poly (N-isopropylacrylamide) Hyrdogels, e.g. Polyacrylamide, poly(propylene oxide Pluronic polyols family of gel materials, e.g. Pluronic-chitosan hydrogels Silica gels

[0205] In addition the pads may include any other natural or synthetic material, which will act to absorb the drug, compound and be able to release the drug upon ultrasonic excitation.

[0206] Having described the invention in the above detail, those skilled in the art will recognize that there are a number of variations to the design and functionality for the device, but such variations of the design and functionality are intended to fall within the present disclosure.