JP2005525147A - Substance delivery device - Google Patents

Abstract

A system suitable for immobilizing substantially adjacent to a surface of a subject so as to deliver at least one substance (15) into the subject from the surface of the subject. The system includes at least one opening (9) for receiving at least one ultrasonic transmission. At least one substance (15) is releasably secured substantially adjacent to the at least one opening (19). To deliver at least one substance (15) from the surface of the subject, the acoustic membrane (11) relative to the at least one opening (19) so as to transmit at least one transmission to the at least one substance (15). ) Is placed.

Description

  The present invention relates generally to substance delivery systems, and in particular to ultrasound enhanced substance delivery devices.

  Generally, transdermal drug delivery systems employ medicinal devices or patches that are applied to the skin of a patient. The patch is capable of absorbing medicinal compounds contained within the patch from the cortex into the patient's bloodstream. Transdermal drug delivery reduces the pain associated with drug infusion and intravenous drug administration, and the risk of infection associated with these techniques. Transdermal drug delivery also avoids gastrointestinal metabolism of the administered drug, reduces drug removal by the liver, and provides continuous release of the administered drug. Transdermal drug delivery also improves patient compliance with drug therapy because it is relatively easy to administer and the drug is continuously released.

  Many medicinal compounds are not suitable for administration by known transdermal drug delivery systems because they are difficult to absorb through the skin due to the molecular size of the drug or other bioadsorption properties of the drug. In such cases, when transdermal drug delivery is attempted, it can be seen that the drug accumulates on the outer surface of the skin and does not penetrate the bloodstream through the skin. One such example in the past is insulin that has proven difficult to administer by transdermal drug delivery.

  Some of the most essential drugs are currently administered by injection or oral mode of administration, but they have several drawbacks. In particular, chemotherapeutic agents are administered in increased amounts because of the need to survive degradation in the gastrointestinal tract. Many important AIDS therapies require a cocktail of drugs that are administered orally in a solid dosage form and are taken several times a day to be effective. These drugs are not suitable for administration by known transdermal drug delivery systems because of the large dosage requirements and the drug molecules cannot remain stable in a transdermal format. Furthermore, it can be said that many drugs are not suitable for conventional transdermal transport because of low bioadsorption of the drug across the skin layer.

  In general, conventional transdermal drug delivery methods have been found to be suitable only for low molecular weight drugs such as nitroglycerin for angina, nicotine for smoking cessation treatment, and estradiol for postmenopausal female estrogen replacement. Insulin (a peptide used to treat diabetes), erythropoietin (used to treat severe anemia), and gamma interferon (used to enhance immune system anti-cancer function) are all conventional dermal It is a compound that does not normally work when used in drug delivery methods.

  However, energy such as ultrasonic energy can be utilized to enhance transdermal delivery of certain drugs. As used herein, the terms `` ultrasound '' and `` ultrasonic '' have their usual meanings, but at least one source is `` ultrasound '', 20 kHz It is defined as a mechanical pressure wave having a higher frequency (Non-patent Document 1). This 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 skin permeability to drug molecules has been termed sonophoresis or phonophoresis.

  The foregoing method of enhancing transdermal drug delivery using ultrasound required that it be used in a clinical ultrasound delivery environment such as a clinic, hospital or clinic. Furthermore, the time to deliver measurable amounts to human skin using these methods ranged from 10 minutes to 24 hours. In this case, the use of ultrasonic transdermal drug delivery therapy may actually be less desirable than simple injection from the point of patient administration. This method is undesirable because it requires the patient to remain on the treatment table while visiting the clinical environment and using ultrasonic therapy to deliver the drug.

  Although it is known to use a specific ultrasonic frequency to enhance the delivery of a specific drug in a specific application, the results in that application were significantly disappointing. In many cases, the drug delivery route, an effective initial amount of drug that penetrates the skin, was used, but as the time of applying ultrasound to the same spot on the skin increases, the delivery rate gradually decreases or decreases to zero. There was.

  Ultrasound exposure has been continuous or intermittent to reduce overheating of biological membranes. Since the depth of penetration of ultrasound energy into living soft tissue is inversely proportional to frequency, high frequencies improve drug penetration into the skin by concentrating the effect on the outermost layer of the skin, the stratum corneum Was suggested. Agents that are delivered sonically may require variable frequencies and intensities in order to deliver a therapeutically effective amount of the drug to the patient. Depending on the fat content and the mass of the particular patient's tissue through which the drug is delivered, the frequency and intensity to obtain an effective dosing treatment can vary.

  Portable programmable devices and methods for ultrasonic enhancement of substance delivery through the surface of a subject are not disclosed. Conventional ultrasonic methods are inefficient and unsafe, and thus no useful device has been proposed for transdermal delivery of drugs using ultrasonic waves.

In the past, little effort has been expended in designing transdermal patches suitable for ultrasonic drug delivery. Conventional methods employ ultrasonic applicators or sonicators that are applied to the skin tissue that places a collection of target drug on the skin surface under the tip of the transducer. The method of ultrasonic drug delivery is not considered suitable for commercial use. Another example of pre-sonicating the skin and then placing a patch on the sonicated skin area is a passive drug delivery based on the concept of enhanced permeation achieved by ultrasonic transmission. Adopted. This is also not commercially suitable due to the length of time it takes to sonicate the skin and other factors.
H. Lutz et al., Manual of Ultrasound 3-12 (1984)

  In view of the aforementioned problems and / or drawbacks, the development of devices for safely increasing skin permeability for non-invasive drug delivery in a faster time frame represents a major advance in the art. Providing ultrasonic programmable devices and methods that can be used for drug-containing patches is another major advance in the art. In addition, to date, patient mobility, along with continuous release of a wide range of drugs, has been a difficult goal for transdermal drug delivery devices. Thus, suitable transdermal patch designs that accommodate active ultrasonic transdermal delivery methods are useful in achieving commercial ultrasonic drug delivery devices.

A system suitable for immobilizing substantially adjacent to a surface of a subject for delivery of at least one substance from the surface into the subject;
At least one opening for receiving at least one ultrasonic transmission, wherein the at least one substance is releasably secured substantially adjacent to the at least one opening;
A sonic member positioned relative to the at least one aperture to transmit at least one transmission to the at least one substance so as to deliver the at least one substance from the surface of the subject.

  The invention will be more readily understood in conjunction with the non-limiting accompanying drawings.

  While the ground and description of the present invention have been simplified to show elements suitable for a clear understanding of the present invention, many other elements found in the substance delivery system have been omitted for the sake of clarity. You should understand that. One skilled in the art will appreciate that other elements are desirable and / or necessary to practice the present invention. However, since the elements are well known in the art and they do not help a better understanding of the present invention, description of the elements is omitted here.

  The present invention relates to a patch that can be employed in an ultrasonic drug delivery device ideally worn by a patient.

  According to one embodiment of the present invention, a transdermal patch for enhancing transdermal drug delivery through the use of ultrasound is provided. As used herein, the terms “drug” and “substance” can be used together or interchangeably to transmit through a surface or membrane, including but not limited to tissue and other types of membranes. Can include, but is not limited to, substances that can include, but are not limited to, drug or non-drug substances. The use of ultrasound delivers larger pharmaceutically active compounds and transdermal patches meet the special needs of both ultrasound excitation through the patch structure and delivery of drug compounds contained within the patches. This is particularly effective when configured as described above.

  According to one embodiment of the present invention, a transdermal delivery device or patch with a substance that delivers ultrasound contained through the patch and that is used in conjunction with the ultrasound drug delivery method to deliver the drug contained within the patch. To design. Transdermal patches can contain substances such as, for example, certain drugs or cocktails of drugs for disease treatment or pain relief. The sonic applicator can be placed in the vicinity of the patch, for example in the top surface of the patch or in the patch pocket, or can be included in the patch structure itself. When the sonic applicator is activated by an external timing circuit and driver mechanism, or other suitable electronics, the sonic applicator generates ultrasonic vibrations or transmissions through the transdermal patch. The effects of the energy of the ultrasound signal, including but not necessarily limited to vibrations that occur in the patient's skin, enhance the absorption of the drug emanating from the transdermal patch and from the skin to the patient's bloodstream.

  In accordance with one embodiment of the present invention, the introduction of an ultrasound signal into a transdermal patch includes a large molecule drug, a nutrient solution, and a protein that was previously impossible to deliver through a transdermal system. More types of drugs can be employed in transdermal delivery systems.

  In accordance with an embodiment of the present invention, a system employing ultrasound to enhance drug delivery when using an ultrasound applicator device for a transdermal patch, typically in a hospital, clinic or clinic Unlike systems where patients require the assistance of a medical professional, the drug delivery system is fully portable.

  In accordance with one embodiment of the present invention, the system is programmed to provide constant drug delivery at a specific dosage, or intermittent timed delivery, increasing flexibility and controllability for specific patient administration needs. Can do. Conventional transdermal drug delivery systems are generally steady-release devices that provide a full-size treatment response that is not suitable for drug treatment of all patients.

  According to one embodiment of the invention, ideally a patient can wear and / or utilize ultrasound to control transdermal and / or transmucosal flow rates of drugs and other molecules to the body. Transdermal patches can be employed in ultrasonic drug delivery devices that are programmable devices.

  According to one embodiment of the present invention, a method is provided for non-invasive delivery of molecules, including but not necessarily limited to bioactive molecules, from the skin or mucosa using ultrasound and transdermal patches. Is done.

  According to one embodiment of the present invention, various ultrasonic frequencies, intensities, amplitudes and / or phase modulations are applied to control the magnitude of the transdermal flow rate from the patch to achieve a certain therapeutic or nutritional level. be able to.

  According to one embodiment of the present invention, ultrasonic energy is transmitted with high enough efficiency to penetrate the drug, and contains an absorbent material that holds the drug in the patch until released by ultrasound. A transdermal patch is designed.

  According to one embodiment of the invention, a transducer or transducer array can be incorporated into the patch. According to one aspect of the invention, the transducer can be removably inserted into the patch.

  According to one embodiment of the present invention, ultrasound can be combined with chemical enhancers such as iontophoresis, electroporation, hair removal agents, and / or surfactants to promote transdermal permeability.

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

  FIG. 1 is a diagram illustrating one embodiment of this transdermal drug (or other desirable substance) delivery system 100 of the present invention. The transdermal drug delivery system 100 includes an ultrasonic applicator 1 that is placed in the functional vicinity of a transdermal delivery device or patch 2. The patch 2 containing the substance to be delivered is placed in a functional proximity so that it typically contacts the exterior of the patient's skin 3 by a strap or other suitable stabilization device 4, and the strap 4 is ultrasonically Holding device 1 and patch 2 are held in the desired vicinity. The power for the ultrasound applicator 1 is ideally rechargeable and can be placed inside the strap 4 itself or at any other convenient location considering a fixed portable transdermal drug delivery system 100 Provided by a battery or other suitable power source (not shown). For example, the power source can be included within the ultrasound application device 1 itself or provided by an external delivery source.

  The disclosures of each of which are incorporated herein by reference, all filed on August 24, 2001, co-assigned copending US patent application Ser. No. 09 / 939,435, titled “ULTRASONICALLY ENHANCED SUBSTANCE DELIVERY METHOD Reference is made here to "and U.S. Patent Application No. 09 / 939,507, title" ULTRASONICALLY ENHANCED SUBSTANCE DELIVERY SYSTEM AND DEVICE ".

  FIG. 1 is a diagram illustrating use in the arm of a patient according to one embodiment of the present invention. Alternatively, the system can be placed in contact with other parts of the patient's body as determined by medical personnel or other persons managing drugs or other substance therapies. Such locations include, but are not limited to, the patient's chest (eg, for nitroglycerin drug delivery), abdomen, neck, back and feet.

  FIG. 2 shows the structure of human skin and shows various structures including the skin. According to one aspect of the invention, drug or other substance delivery can be performed by moving one or more hair follicles into the substance. In such embodiments, the delivery can occur in the hair follicle of the skin, which can significantly increase the delivery rate of large molecule drugs or other substances. This finding can also be achieved by using ultrasound or by incorporating both sawtooth and square waveforms. More specifically, in this embodiment, the follicular sebaceous gland surrounding the hair follicle can be enlarged by this substance delivery method. When the penetrating drug substance moves through the hair follicle and reaches the hair root, the hair root Absorbed into the bloodstream located in the vascular network just below This substance pathway delivers more substance ultrasonically than simply utilizing the cavitation effect on the skin surface that leads to microporosity of the skin tissue, or simply storing the drug on the skin and moving open skin pores. It is possible.

  In one embodiment, patch 2 is used for the purpose of enhancing penetration of substances such as drug compounds (drugs) contained within the patch into tissues such as skin or mucous membranes or other membranes and into the patient's bloodstream. Can be subjected to ultrasound. The drug compound is more suitable for the patient in a continual method (hereinafter referred to as “continuous release”) or intermittent method (hereinafter referred to as “intermittent release”) for drug treatment or other therapies for a particular patient. The ultrasonic drug delivery system 100 can be programmed to deliver in a manner that appears to be present.

  FIG. 5 is a diagram illustrating one embodiment of an ultrasound signal that results in enhanced substance delivery of the present invention. The signal in FIG. 5 employs a combination of a sawtooth waveform and a square wave. In this embodiment, the tip of the sawtooth homogenizes the drug contained within the patch, and the subsequent square wave delivers ultrasonic energy to the surface of the skin for skin transmission.

  As described above, FIG. 2 is a diagram generally showing a typical structure of human skin. Examples of the route from the skin to the bloodstream include the following.

  1. Penetrates into the stratum corneum.

  2. Permeate the drug through the skin's sweat pores.

  3. Permeate the drug through the skin by reaching the hair root through the follicular sebaceous pore and then entering the vascular network located at the base of the hair root.

  In one embodiment of the present invention, transdermal drug delivery can be performed by utilizing the drug pathways associated with the sweat pores and hair follicle system of the patient's skin. In one embodiment, the ultrasound frequency, intensity level and waveform are adjusted to maximize drug delivery, primarily through the follicular pathway, secondarily through the skin surface sweat pores and not necessarily directly through the stratum corneum. Can be. The amount of energy required to penetrate the stratum corneum is excessive and is believed to damage adipose tissue. In this embodiment of the present invention, this transmission through the patch and through the skin follicles and sweat pores can be enhanced by employing either or both of the following forces that can act on the skin surface: it can.

1. First, in one embodiment, applying a compressive force or tension to the surface of the skin can cause the skin to contract and make the drug pathway more noticeable. Referring to FIG. 1, it can be seen that the strap holds the device to the patient's arm. In addition to securing the device to the patient's body, the strap applies pressure to the surface of the skin and causes the skin to contract. The contraction caused by a tight strap can cause 1) a downward pressure perpendicular to the skin surface to act on the skin, and 2) the skin can be more easily passed through skin pores such as sweat and / or follicular sebaceous pores. It may be possible to influence the permeability of the skin by changing the position of fat or other tissue located under the outer skin layer so that transdermal delivery is enhanced and / or 3) Thus, it provides a more substantial drug delivery route than could be obtained by prior art methods that employ excessive cavitation energy on the skin surface to penetrate the stratum corneum.

2. Secondly, a force, which is the pressure generated by the ultrasound signal, is applied to the skin. It is believed that the use of alternating waveforms can provide a pressure wave effect on the skin and enhance drug delivery through the hair follicle and sweat system while minimizing the amount of energy transferred to the skin surface. . Referring to FIG. 5, one embodiment employs a waveform that alternates from a sawtooth wave to a square wave. The amplitude and intensity of the shaping wave helps to miniaturize the beadlet size of the active drug substance in the patch, and the homogenization of the drug contained in the transdermal patch (as seen in FIGS. 3 and 4). It is thought to be useful for both drug delivery through the skin. The peak portion of the serrated ultrasound waveform facilitates drug homogenization without imparting destructive frequencies and cavitation to the drug substance. When converted to a square wave, ultrasound transmission serves to massage and release the fatty tissue surrounding the hair follicles and sweat pores. Drugs that penetrate from the transdermal patch have a monomeric form and / or are reduced in droplet size and are more appropriately dimensioned to penetrate the skin. In one embodiment, the droplet size can be reduced to less than approximately 50 angstroms. The square wave “pushes” the drug through the hole and along the hair follicle, and the drug travels to the hair root and enters the bloodstream directly through the vascular network.

  Ultrasound parameters that can be varied to improve or control penetration include (1) frequency, (2) intensity, (3) exposure time, and / or (4) ultrasound waveform. However, it is not necessarily limited to them. All of these parameters can be simultaneously modulated in a complex fashion to increase the effectiveness or efficiency of ultrasound associated with increasing transdermal molecular flow rates in or out of the human body.

  Ultrasound attenuates rapidly in air, so using coupling agents, for example, coupling agents that have the lowest possible absorptivity, which are non-colorable, non-irritating, and dry slowly, Ultrasonic energy can be efficiently transmitted from the ultrasonic transducer to the skin. When chemical enhancer fluids or anti-irritants or both are employed, they can function as coupling agents. For example, glycerin used as an anti-irritant can also function as a coupling agent. If necessary, additional components can be added to the enhancer solution to increase the efficiency of ultrasonic transmission. In one aspect of the present invention, a resonance-reactive gel can be used to further enhance drug delivery through the skin. In addition, bioactivity can be enhanced utilizing the maintenance of the drug in a sterile and non-degraded form.

  In one embodiment of the present invention, the transdermal patch 2 can operate in conjunction with the sonic applicator 1 to perform ultrasound-enhanced transdermal delivery of a desired substance. In particular, efficient energy transfer can be ensured by adjusting the contact between the applying device 1 and the patch 2. The material used to construct the patch can be selected to maintain the strength and power output of the ultrasonic transmission from the transducer to the transdermal patch. The present invention is particularly suitable for delivering large molecule materials. For example, insulin has a large molecular size and generally forms hexamers of 50 angstroms or more, making it difficult to penetrate skin pores. Insulin molecules tend to aggregate when they accumulate. Therefore, the insulin accumulated in the patch pocket tends to agglomerate to a larger drug mass size, thus reducing the ability to transmit skin.

  In order to help alleviate this problem and keep the drug small enough for skin transmission, a square wave can be used from the sawtooth waveform and the waveform of the ultrasound signal delivered by the applicator device 1 can be changed from time to time. FIG. 5 is an illustration of an alternating waveform concept where the sawtooth waveform is more efficient at homogenizing the drug in the patch and skin transmission is enhanced as the ultrasound waveform switches to a square waveform. Under the sawtooth waveform, high energy is provided in a short time, and the pressure amplitude is reduced, resulting in a vibration effect on the drug substance of interest. This vibration is low heat and has the effect of mixing or homogenizing the drug in the patch. Smaller beatlet sizes are possible due to the sawtooth waveform.

  Referring now to FIGS. 3 and 5, when the sonic transmission is converted to a guided square wave, more energy is released through the patch and is homogeneous in the semi-permeable membrane 13 which can be part of the patch fixed to the surface of the skin. Ingested chemicals. Therefore, as shown in FIG. 2, the intensity of sound wave transmission acts on the hole directly along the hair follicle. Square waves allow holes that open directly along the hair follicle to “open” and increase susceptibility to drug transmission. The deposited drug moves downward along the hair follicle, reaches the basal root of the vesicle through the epidermis, and accumulates as it is in the bloodstream inside the vascular network of the skin. Deposited drugs circulate in the body from there.

  Referring now to FIG. 1, it can first be seen that the transdermal patch 2 is placed in a functional neighborhood, for example in contact with the patient's skin 3. In one embodiment of the invention, the patch 2 can be applied to the skin 3 by an adhesive or other suitable means. Functions of patch 2 such as touching patch 2 so that sonic applicator 1 generates an energy signal, eg, an ultrasonic signal across transcutaneous patch 2 under sonic applicator 1 Can be placed near the target. The material contained within the transdermal patch 2 can be homogenized into smaller droplet sizes, thereby allowing the material to more easily diffuse into the skin. The ultrasound signal can also affect the skin tissue by breaking down and / or breaking down skin fat to deliver the substance. Alternatively, the hair follicle tract can function as a substance delivery tract. Regardless of the mechanism, the material affected by the ultrasound signal penetrates the surface of the skin, passes through various layers of skin and adipose tissue, and is ultimately absorbed into the patient's bloodstream and / or tissue.

  FIG. 3 is a diagram illustrating one embodiment of the transdermal patch 2 of the present invention, referred to herein as “Patch A”. The transdermal patch 2 is composed of a backbone or backing material 10 in which a part or opening is formed, and a sonic membrane 11 is incorporated in the upper part of the patch 2. Release film 12 seals patch 2 until use. Release film 12 comprises any suitable material including, but not limited to, an ultraviolet resistant antistatic polyethylene film (thickness: 50 micrometers) available from Crystal-X Corp. (Sharon, PA). can do. At the bottom of the patch 2 is a semi-permeable member 13 such as a membrane or film that comes into functional proximity of the skin, such as coming into direct contact with the skin in use. Inside the patch 2, the absorbent pad 14 holds the desired drug or drug compound 15. The ultrasonic signal first passes through the absorption pad 14, is transmitted through the acoustic film 11, and passes through the patch 2. A drug or other substance 15 is contained within the absorbent pad 14 until released by an ultrasonic signal or other means. The material then permeates through the semipermeable membrane 13 and deposits on the surface of the patient's skin.

  FIG. 4 is a diagram showing another embodiment of the transdermal patch 2 of the present invention, referred to herein as “Patch B”. A gasket 16 is disposed between the backbone 10 and the absorbent pad 14. The gasket 16 can be composed of any suitable material such as, for example, synthetic rubber. The gasket 16 forms a liquid reservoir or well on which the absorbent pad 14 is disposed. As the skin is pushed up, the gasket 16 forms a barrier that prevents moisture and air from moving under the patch and interfering with the ultrasonic signal intensity. Alternatively, a sealant compound, ultrasonic gel or other suitable material may be used on or in place of gasket 16 to provide a sealing action near the boundary of patch 2 to provide waterproofing, a substance or drug patch Prevent leakage from the air and prevent air from getting under the patch.

  Referring now to FIG. 6, the transducer 18 can be incorporated directly into the patch 2 or in any other suitable location. In such a configuration, a single transducer can be employed, or an ultrasonic transducer array may be desired.

  FIG. 7 shows the lower side of the patch 2 and shows the well 17 together with the semipermeable membrane 13 on the absorption pad 14. Alternatively or in addition, a sealing gasket or compound 16 can be placed in the lower well 17 of the patch 2.

  Referring now to FIG. 8, according to one embodiment of the present invention, immobilization is substantially adjacent to the surface of the subject so as to deliver at least one substance from the surface and into the subject. A patch or system 2 suitable for doing so is provided. The system 2 can include a backing layer, backing material, backbone or backbone material 10 and at least one opening 19 formed in the backing layer 10 for receiving at least one ultrasonic transmission. The system 2 can further include a pad 14 such as an absorbent pad that releasably secures at least one substance substantially adjacent to the at least one opening 19. A sonic member 11, such as a sonic membrane or film, is positioned relative to at least one opening 19 and at least one to at least one substance so as to effect said delivery of at least one substance from the surface of the subject. Can communicate. In some cases, a semi-permeable member 13 such as a membrane or film or a valve layer can be provided.

  In one embodiment of the present invention, a composite frequency of sawtooth and square waves as shown in FIG. 5 is used to transmit the ultrasonic signal, thereby first homogenizing the material 15 in the patch 2 and then It is believed that skin transmission occurs when substance 15 is deposited on the surface of the skin. It is not necessary to use a coupling agent between the skin and the semipermeable membrane.

  According to one embodiment of the present invention, the substance 15 released from the absorbent pad 14 can be stored on the surface of the skin. This storage material can serve to further improve sonic transmission by acting as a sonic coupling agent. According to one embodiment of the present invention, the storage material can be reabsorbed by the absorbent pad 14.

  Referring again to FIGS. 3 and 4, the acoustic transmission generated from the transducer 18 passes through the acoustic membrane 11, then the absorbent pad 14, and then through the patch 2 onto the patient's skin and / or through the skin. The acoustic membrane 11 can be constructed of any suitable resonance compatible material that allows for this. The acoustic membrane 11 can be composed of any suitable resonant compatible material that provides ultrasonic transmission without significantly reducing the effects caused by the transmission of frequency or intensity potential. Suitable resonant compatible materials used for the acoustic membrane 11 include, for example, model numbers Dow BLF-2014, Dow BLF-2015, Dow BLF-2023, Dow BLF- available from Dow Chemical Company (Midland, Mississippi). Polyvinylidene chloride plastic film, such as 2050, Dow BLF-2052, Dow BLF-2057 and Dow BLF-2080, including but not necessarily limited to the film marketed as Saran®, and polyester film For example, Mylar® film, including but not limited to model numbers M30, M33, M34, D887, MC2 and SBL-300, available from DuPont Teijin Films Division (Wilmington, Del.) Can be mentioned, but is not limited thereto. Polyvinylidene chloride films have been found to be effective as sonic membrane materials, but many other materials can provide similar functions. The material of patch 2 can be selected or made to match the resonance compatibility with the desired frequency and intensity of the ultrasound used for the skin transfer kinetics of a particular substance or drug.

  In one embodiment of the present invention, the sonic membrane 11 can be affixed to the absorbent pad 14 with a suitable resonance compatible material including, but not limited to, a flat layer or a polymer epoxy. One suitable material is a polyurethane material such as Uralite® available from H.B. Fuller (St. Paul, Minn.).

  Absorbent pad 14 absorbs or retains drug 15 while housed within patch 2, but non-woven cellulose fiber or the like that will release drug 15 when an ultrasound signal is transmitted through patch 2 It can be composed of any suitable material, such as any material that acts on. Other materials that can be used include, but are not limited to, natural sponges, fused quartz, and various woven and non-woven materials. Examples of suitable materials include CoTran 9729, a non-woven polypropylene material available from 3M (St. Paul, Minn.), Pop-Up Compressed Sponge (76% cellulose, available from Clipper Mill, San Francisco, Calif.). From Microdon Web, model number M-261420025, Buckey Absorbent Products (Memphis, TN), a non-woven polyester fiber blend available from 3M (St. Paul, MN), including 7.7% polyol, 15.5% sodium chloride) Vizorb # 3010, a cellulose pad containing wood pulp and ethylene vinyl acetate synthetic latex available, and cellulose containing wood pulp and ethylene vinyl acetate synthetic latex available from Buckey Absorbent Products (Memphis, TN) -Vicell # 6009 is a pad, but is not limited to them.

  A semi-permeable membrane 13 can be placed on the bottom of the patch 2 so that it directly contacts the patient's skin. The semipermeable membrane 13 can function like a valve and allows the drug 15 released from the absorbent pad 14 to pass through the semipermeable membrane 13 only by active generation of ultrasound. In the absence of an ultrasound signal, the semi-permeable membrane 13 prevents large amounts of drug from penetrating the membrane and reaching or passing through the surface of the patient's skin. The valve action of the semipermeable membrane 13 can provide a means to control the dosage delivered to the patient. It is believed that the sonicated portion of the skin can maintain permeability to a delivery substance such as a drug for a period of time after the ultrasound signal has disappeared. In this case, if the drug 15 tries to reach the skin, the skin will continue to absorb the drug even after the ultrasonic signal has disappeared. Assuming that a stable delivery rate can be achieved with an active ultrasound signal, the delivery of the correct dosage will be proportional to the time (in seconds or minutes) that the active ultrasound signal has been on the skin surface. As such, the dosage of drug delivered corresponds to the timing of the active ultrasound signal.

  If continuous skin penetration occurs after the disappearance of the active ultrasound signal, it will be difficult to ascertain the exact amount of medication actually delivered to the patient. Thus, a valve patch can be provided that effectively stops drug delivery when the ultrasound signal disappears. For example, so that patch 2 delivers a drug only in the presence of an ultrasound signal at the timing of delivering the proper dosage by the timing circuit of sonicator device 1 shown in FIG. A membrane 13 can be used at the base of the patch 2.

  The semipermeable membrane 13 can be constructed using a suitable elastic material that changes properties when exposed to changes in pressure and / or temperature. In one embodiment of the present invention, the semipermeable membrane 13 can be any suitable material including but not limited to natural sponge and porous polymer film. The ultrasonic signal is believed to create a cavitation effect in the polymer film and increase the film's permeability by enlarging the film's pore diameter. In the absence of an ultrasonic signal, the elasticity of the film causes it to return to its original structure, and by reducing the diameter of any pores, macromolecular substances contained in Patch 2 can be further transferred from Patch 2 to the skin. Stop being transmitted.

  According to one embodiment of the invention, in the absence of an ultrasound signal, any suitable solution that does not diffuse the drug-containing solution into the membrane and diffuses the drug solution into the membrane when subjected to the action of the ultrasound signal. The semipermeable membrane 13 can be made of a semipermeable material.

  According to one embodiment of the present invention, the semipermeable membrane 13 can be composed of any suitable thermoplastic material. The material can change its properties when the temperature rises as a result of ultrasonic vibration, and can return to its original state when the ultrasonic signal disappears. According to one embodiment of the present invention, the transmission characteristics are changed when subjected to the action of the ultrasonic signal, allowing the drug to move through the membrane, and when the ultrasonic signal disappears, the original transmission state is substantially reduced. The semipermeable membrane 13 can be composed of any suitable thermoplastic elastomer that returns.

  According to one embodiment of the present invention, the semipermeable membrane 13 can be composed of any suitable ionomer (ion-containing polymer) that includes, but is not necessarily limited to, an ionomer that functions as a thermoplastic elastomer. According to one embodiment of the present invention, suitable ionomers include ethylene methacrylic acid (such as a film marketed as Surlyn® available from DuPont (Wilmington, Del.)). Although a copolymer is mentioned, it is not necessarily limited to it.

  When transdermal patch 2 releases the contents of drug 15, patch 2 can be replaced with a new patch 2. A new patch 2 can then be employed over other drug delivery periods. Alternatively, additional amounts of substance or drug can be inserted into patch 2 by suitable means to effectively “refill” the patch. In one embodiment, when the patch 2 is replaced, it can be removed from the transducer assembly 18 or other delivery source of the ultrasound signal.

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

  Alternatively, the transducer 18 can be slid into the top of the patch using, for example, a pleat on the top of the transdermal patch 2. As shown in FIG. 6, the transducer 18 can be incorporated directly into the structure of the patch.

  The backbone 10 of the patch 2 can be composed of any suitable material including, but not limited to, polyolefin film or polyvinyl chloride. Examples of suitable materials include polyvinyl chloride foam tape 9772-L available from 3M (St. Paul, MN), and adhesive lined polyolefins available from 3M (St. Paul, MN). Model number 3M9773 foam tape, which is a foam tape. Backbone material 10 can have an adhesive, such as a pressure sensitive acrylate adhesive used in 3M9772-L foam tape available from 3M (St. Paul, Minn.), For example, and patch 2 can be applied to the patient. Allows to adhere to the surface of the skin.

  In accordance with one embodiment of the present invention, a backing member 10 comprising model number 9772-L foam tape (3M, St. Paul, MN) is a Saran® film, model number Dow BLF-2014 (Dow It includes at least one aperture covered by a sonic membrane 11 including Chemical Company, Misland, Mississippi), or Mylar® film, model number M34 (Dupont Teijin Film, Wilmington, Del.). At least one absorbent pad 14 containing cell source material (model number Vicell® # 6009, Buckeye Absorbent Products, Memphis, TN) is positioned so that ultrasonic energy is transmitted through the acoustic membrane 11 to the absorbent pad 14 Can be done. Insulin solution (Humulin® R, Eli Lilly, Indianapolis, Ind.) Contained on or in the absorbent pad 14 in the presence of an ultrasound signal is Surlyn® (DuPont, Wilmington, Del.). The translucent membrane 13 can be moved and delivered to the subject. Release films 12 including UV resistant antistatic polyethylene film (thickness: 50 micrometers) (Crystal-X, Sharon Hill, PA) can be used.

  According to one embodiment of the present invention, the patch 2 can completely transmit an ultrasonic signal. Therefore, it can be said that it is desirable to minimize the attenuation of the ultrasonic signal when the ultrasonic signal moves through the material of the patch 2. Of particular concern is a pocket located in the absorbent material used for patch 2, for example containing air, gas or moisture, which can subsequently act on the frequency and / or intensity of the transmitted ultrasound signal. is there. To facilitate improved ultrasound transmission of the patch, the absorbent material can be treated using vacuum lyophilization to remove trapped air from the absorbent material. In this method, the material is frozen by lyophilization and then vacuum dried. One effect of lyophilization is to reduce the amount of trapped air in the tissue of the absorbent material, making it more resonant compatible with the frequency and intensity of ultrasonic transmission and improving its damping characteristics That is.

  According to one embodiment of the present invention, the absorbent pad material can be immersed in a 0.9% NaCl aqueous solution prior to the lyophilization process. Pretreatment with saline leaves a residue of NaCl in the absorbent material. The salt residue acts as a wetting agent, adsorbs water and maintains some moisture in the absorbent pad. By preventing the absorbent material from drying, it becomes possible for the drug stored in the pad to remain in the solution, thereby preventing a decrease in moisture that causes the drug solution to have a high concentration. Concentration of drug solutions that can cause aggregation or precipitation of the active drug and inhibit drug delivery can be avoided.

  Suitable materials for the absorbent pad can have one or more of the following characteristics.

1) High absorbency for selected drugs present in the form of emulsions or solutions.

2) Absorbing materials are inert to excipients or preservatives used for selected drugs or drugs in solution over a long shelf life.

3) The absorbent material is resistant to degradation by exposure to ultrasound and released contaminants to stored drugs.

4) Absorbent material is substantially free of metal, organic or inorganic contaminants.

5) Absorbent materials are not irritating to human skin and remain stable even when interacting with human sweat.

6) The absorbent material remains stable in stored form for over a year and is resistant to degradation over time when immersed in the drug.

7) The absorbent material can be composed of natural or synthetic material.

  According to one embodiment of the present invention, the absorbent material is a superabsorbent defined as a material capable of absorbing a liquid with a weight of 14 times or more of its weight. The superabsorbent material gives the pad the ability to store the drug in a diluent or suspension. This can be particularly important for polypeptides such as insulin that are thought to form multimeric structures when concentrated in solution. By preventing the absorbent pad from drying out and thus maintaining the insulin in the form of a dilute solution, the insulin is maintained in the form of a monomer that is most easily transmitted from the patch to the skin.

  According to one embodiment of the present invention, the absorbent material contains a functional group capable of cross-linking with the drug. The cross-linking can serve to stabilize the drug stored in the patch 2. When an ultrasound signal is applied to the patch 2, the ultrasound signal can break the cross-links so that when it reaches the absorbent material, the drug is released from the absorbent material and freely delivered to the subject.

  According to one embodiment of the present invention, the absorbent material forms a crosslink with the drug, but when the drug is subjected to the action of an ultrasonic signal so as not to form a crosslink that destroys the original structure of the drug, The absorbent material can be formed from a material that includes a modest amount of cross-linking points so that it does not bond to the absorbent pad 14 and breaks the cross-link so that it is freely delivered to the tissue of the subject.

  According to one embodiment of the present invention, the absorbent material and the drug are cross-linked through hydrogen bonds.

According to one embodiment of the present invention, the absorbent material contains a functional group capable of forming hydrogen bonds with a functional group of a polypeptide drug such as insulin. In this case, the hydrogen bond serves to stabilize the structure of the drug. When subjected to the action of an ultrasonic signal, the hydrogen bonds that crosslink the drug with the absorbent material are broken, without breaking the hydrogen bonds that form aspects of the original secondary structure or polypeptide structure.

  Table 1 lists at least some of the materials that can be used to construct the absorbent pad 14.

Examples of materials Suitable materials for absorbent pad 14

  According to one embodiment of the present invention, the absorbent compound may be a nonwoven material having a suitable amount of functional groups available for cross-linking. When the absorbent material contacts the drug, the functional group of the absorbent material forms a crosslink with the drug so that the structure of the drug is stable in the absence of ultrasound signals. When the ultrasound signal is transmitted through the patch to the absorbent material, the crosslinks can be broken so that the drug is released from the absorbent material without causing contamination or destruction of the drug's native structure.

  According to one embodiment of the invention, the absorbent material is processed by freezing and then vacuum dried. The lyophilization of the absorbent material serves to reduce the amount of contaminants such as air or moisture that can be incorporated into the absorbent material. The contaminants may react with the functional groups of the absorbent material and prevent these functional groups from forming crosslinks with the drug. Upon lyophilization, the contaminants are removed and the cross-linking sites of the absorbent material are released so that the cross-linking sites are free to form cross-links with the delivered material. In addition, lyophilization can also remove contaminants that react with or contaminate the drug.

  According to one embodiment of the present invention, the absorbent material retains the drug in the absence of an ultrasonic signal and can release the drug when excited by the ultrasonic signal and the ultrasonic signal disappears Any excess drug that subsequently remains on the skin surface can have absorption properties such that it is reabsorbed by the absorbent pad and not released until other ultrasound signals are transmitted to the absorbent material. This function of the absorbent material allows for tight control of the delivered drug dose by the parameters of the ultrasound signal and can eliminate the need for a semi-permeable “valve” membrane to control the dosage. According to embodiments of the present invention, a material having the ability to absorb a drug solution of about 1 to about 4 times its weight is suitable for absorption / release / regeneration that allows for controlled dosage release by ultrasound. Absorption characteristics can be provided. The absorption rate can be adjusted by manufacturing the absorbent material using different types and combinations of fibers. For example, cellulosic materials can be made from fibers derived from various types of wood (eg, “hard” and “soft” wood) having different absorption characteristics.

  According to one embodiment of the present invention, when an ultrasonic signal is transmitted through the patch 2, the signal massages the hole directly surrounding the hair follicle and increases the permeability of the hole. The ultrasound signal enhances the transmission of the drug 15 stored in the absorbent pad 14 in the patch 2 through the semipermeable membrane 13 and accumulates the drug 15 on the skin surface, where the drug 15 passes through the hair follicle. It moves down to the hair root and is absorbed by the body by entering the vascular network.

According to one embodiment of the present invention, the ultrasonic transmission can have a frequency in the range of about 20 kHz to about 10 MHz. The intensity of the ultrasonic wave transmission may be in the range of about 0.01 W / cm ² to about 5.0 W / cm ^2. As the frequency and intensity level change, it is necessary to change the materials used to construct the transdermal patch 2 to take into account optimal performance in both drug delivery and the valve function achieved by the semipermeable membrane 13 In some cases.

  According to one embodiment of the present invention, a waveform that is converted from sawtooth to square has been described, but a conventional sinusoidal waveform may also be effective as a drug delivery waveform for ultrasonic transmission.

  The devices and methods according to the present invention are useful for delivering a wide range of substances to a patient. As described in more detail herein, for example, a substance can be delivered transdermally, intracavity, and into a solid tissue site, in each case the substance, or its pharmacological Absorption into the tissue below or around the active part is enhanced by application of ultrasound or sonic energy. The substance can take any suitable form including, but not limited to, a liquid, gel, porous reservoir, or insert, and the substance or its pharmacologically active portion can be, for example, an existing Can be treated or alleviated, or other conditions of the patient can be prevented or suppressed. The effect of the substance may be local as in the case of anti-tumor treatment or systematic. Suitable agents include, but are not limited to, a wide variety of compounds that are usually delivered through the skin and other novice surfaces or to solid tissues.

  In general, the drug is not particularly limited, but can include or incorporate the following substances. That is, anti-infectives such as antibacterial agents and antiviral agents, analgesics and analgesic compounds, appetite suppressants, anti-helminths, antidiabetics, antidiarrheals, antihistamines, anti-inflammatory agents, anti-migraine agents, anti-emetics Antitumor, antiparkinsonian, antipruritic, antipsychotic, hypothermic, antispasmodic, anticholinergic, sympathomimetic, xanthine derivatives, potassium and calcium channel blockers, beta blockers and anti Cardiovascular drugs, including but not limited to arrhythmic drugs, antihypertensives, diuretics, vasodilators including whole coronary arteries, peripheral and cerebrum, central nervous system stimulants, antitussive and cold drugs including decongestants, estradiol Steroids including, but not limited to, hormones, hypnotics, immunosuppressants, muscle relaxants, parasympathies including but not limited to corticosteroids Through stimulants, psychoactive agents, sedatives, as well as a tranquilizer. The methods of the present invention can deliver high or low molecular weight drugs as well as ionized and non-ionized drugs.

  Proteinaceous or polypeptide drugs represent a group of drugs suitable for use with the invention disclosed herein. Such drugs cannot generally be administered orally in that they are often destroyed in the gastrointestinal tract or metabolized in the liver. Furthermore, because most of the polypeptide drugs are high molecular weight, they are generally not effective for conventional transdermal delivery systems.

  General examples of drugs or nutritional compounds that can be included in the transdermal patch 2 of the present invention include acetaminophen, antibodies, aspirin, corticosterone, erythromycin, ibuprofen, insulin, nitroglycerin, nicotine, progesterone. , Estrogen, steroids such as estradiol, and vitamins, but are not limited thereto. Suitable forms of insulin include, but are not necessarily limited to, Humulin® and Humulog®, both available from Eli Lilly and Company (Indianapolis, Ind.). Any other substance may be utilized including but not limited to drugs and / or nutritional compounds used for functional, medical or pharmaceutical purposes, and any combination thereof. It is desirable to use the methods of the invention in combination with drugs that have a relatively low skin permeability or that provide a lag time. Application of the ultrasound signals described herein has been found to significantly reduce the lag time associated with transdermal administration of most drugs.

  The combined use of ultrasound signals and iontophoresis, i.e., passing an electric current through the skin, has been attempted for various forms of drug delivery. In some cases ultrasound signals were used with iontophoresis, and in other cases ultrasound was a pretreatment for iontophoresis applications. Applicants noted that the method of combining iontophoresis with the device of the present invention can be used to enhance skin molecular transmission.

  The use of chemicals, often called chemical enhancers, can also enhance drug delivery in the present invention.

  According to one embodiment of the present invention, a safety feature can be incorporated that indicates that the patch is empty or has already been used. As a means of indicating that the patch has already been used, an ultrasound contrast agent or colored label that changes color, for example, from green to red, can be used in the patch when exposed to ultrasound.

  According to one embodiment of the present invention, a biosensor that detects a patient's glucose level through invasive or non-invasive means is attached to the transdermal patch 2, and data from the sensor is used to The use of the drug and the timing of drug delivery can be controlled.

  According to one embodiment of the present invention, a biosensor that detects the amount of drug actually delivered to a patient can be attached to the transdermal patch 2. The sensor can measure the electrical resistance of the patient's skin. Delivery of the drug through the skin produces a readable change in the electrical resistance of the skin tissue surrounding the transmission site. Data from the biosensor can be used to record the actual amount of drug delivered to the patient from the patch.

  Referring now to FIG. 9, a transdermal delivery device or assembly 300 according to one embodiment of the present invention is shown. The delivery device can include a transducer coupler 201 that includes a transducer housing 202 in which at least one ultrasonic transducer 18 or transducer 18 array can be disposed. According to one aspect of the invention, the transducer 18 array is 2 × 2 rows. The delivery device can further include a cap unit or patch cap 210 containing an absorbent pad 14 containing at least one substance to be delivered. The acoustic film 11 may be configured as a part of the cap unit 210 so as to cover the absorbent pad 14 on the side disposed in contact with the transducer coupler 201, or attached to the cap unit 210. May be. According to one aspect of the invention, for example, a film commercially available as Saran®, including but not necessarily limited to model number Dow BLF-2014 available from Dow Chemical Company (Midland, Mississippi). The acoustic film 11 can be made of such a polyvinylidene chloride plastic film. According to one embodiment of the present invention, the sonic membrane 11 can have a diameter of about 4.0 cm and a thickness of about 50 μm. According to one aspect of the present invention, a polyester film, such as Mylar® film, including but not limited to model number M34 available from DuPont Teijin Film Division (Wilmington, Delaware) The membrane 11 can be configured. According to one aspect of the present invention, the acoustic film can have a size of approximately 4.0 cm (diameter) × 13 μm (thickness). The release film 12 may be configured as part of the cap unit 210 to cover the side of the absorbent pad 14 that is placed against a substance delivery subject, such as the subject's skin, prior to its removal. Once the release film 12 is removed, the absorbent pad 14 containing at least one substance can be exposed to be fixed adjacent to the substance delivery target.

  According to one aspect of the present invention, the cap unit 210 may optionally include a semi-permeable membrane 13 on the underside of the cap 210 such that the semi-permeable membrane 13 is in functional proximity to the surface of the subject. it can. Translucent with any suitable material, including but not limited to ethylene-methacrylic acid copolymers (such as, for example, a film marketed as Surlyn® available from DuPont (Wilmington, Del.)) The membrane 13 can be configured. According to one aspect of the present invention, the semipermeable membrane 13 can have a size of approximately 4.0 cm (width) × 4.0 cm (length) × 50 μm (thickness).

  The transdermal delivery device can be configured such that the cap unit 210 can be snapped or screwed to the transducer coupler 201 to produce a transdermal delivery device or assembly. Using a screw coupling, a mating connector groove, a bayonet fastening system or other connection coupling system or device (collectively referred to herein as a screw coupling), the cap unit 210 and the transducer coupler 201 are Can be connected. The screw coupling couples the transducer coupler 201 and the cap unit 210 by pivoting or rotating the transducer coupler 201 and the cap unit 210 so that the coupler 201 and the cap unit 210 are substantially coupled. be able to. Examples of screw couplings that can have a single pivot or rotation include configurations similar to those of child proof caps commonly used in pharmaceutical packaging.

  A lead or cable 204 can be used to connect the transducer 18 to the power supply and / or control unit 400 (FIG. 32G) and can be derived from the transducer coupler 201.

  The strap 250 can be used to secure the transdermal delivery device 300 to the subject's body. The pressure generated by the strap 250 connection to the subject can establish an interface between the absorbent pad 14 and the subject's surface. The pressure generated by the strap 250 connection to the subject can be utilized to establish a sonic connection or interface between the absorbent pad 14 and the surface of the subject. The pressure generated by the strap connection 250 substantially prevents leakage of material from under the cap 210 and also substantially prevents contamination of the material being delivered to the surface of the subject. An interface with the surface of the subject can be established.

  According to one aspect of the invention, the cap unit 210 can include internal threading and can be screwed to the transducer coupler 210 that can have external threading. The pressure induced by screwing the cap unit 210 onto the transducer coupler 201 can establish a sonic connection or interface between the transducer coupler 201 and the sonic membrane 11 of the cap unit 210. The pressure induced by screwing the cap unit 210 onto the transducer coupler 201 can establish a sonic connection or interface between the sonic membrane 11 and the absorbent pad 14.

  Alternatively, according to aspects of the present invention, transducer coupler 201 can similarly be screwed to cap unit 210.

  Referring now to FIG. 10, there is shown a transducer coupler 201 suitable for use with the present invention. The transducer coupler 201 can include a housing 202 having at least one transducer cap connector groove 203. The transducer coupler can further include a sonic faceplate 205 designed to form a sonic interface with the cap unit 210 (FIG. 9). According to one aspect of the present invention, transducer coupler 201 may be about 4.0 cm in diameter and about 1.0 cm in thickness and manufactured by Sonic Systems Inc. (Newtown, Pa.). . The housing 202 can be composed of any suitable material. In accordance with one aspect of the present invention, the housing 202 may be composed of plastic components, for example, epoxy sold as Eccobond® 45LV and catalyst 15LV available from Emerson & Cumming (Billerca, Mass.). The sonic faceplate 205 can be composed of any sonic compatible material, such as, for example, a stainless steel plate approximately 4.0 cm (diameter) × 1.0 mm (thickness) available from Sonic Systems Inc. (Newtown, Pa.). .

  Referring now to FIG. 11, a cap unit 210 suitable for use with the transducer coupler 201 of FIG. 10 is shown. Cap unit 210 may be constructed of plastic or any sonic compatible material. The cap unit 210 can include an absorbent pad 14 (FIG. 9) containing at least one substance to be delivered. According to an embodiment of the present invention, the absorbent pad 14 may be composed of a cellulose pad comprising an ethylene vinyl acetate based synthetic latex-containing wood pulp such as Vicell # 6009 available from Buckeye Absorbent Products (Memphis, TN). . According to one aspect of the present invention, the absorbent pad 14 can have a diameter of about 4.0 cm and a thickness of about 0.92 mm. The cap unit 210 is in contact with the subject's skin and substantially prevents the entry of air or contaminants under or into the device and the leakage or contamination of the material deposited on the subject's skin by the transdermal delivery device. An adhesive or sealing ring 213 suitable for forming a seal to prevent can further be included. In accordance with one aspect of the present invention, the adhesive ring 213 can be constructed of foam tape model number 3M 9772-L, which is a back adhesive polyvinyl chloride available from 3M Company (St. Paul, Minn.). According to one aspect of the present invention, the adhesive ring 213 can be composed of model number 3M 9773 foam tape, which is a back adhesive polyolefin film. According to one aspect of the present invention, the adhesive ring 213 can have an approximate dimension of an internal opening of 3.75 cm in diameter and a ring dimension of 0.25 cm × 1.0 mm (thickness).

  The cap unit 210 can have a textured surface 212 on the outer surface of the cap 210 to improve the grip and rotation performance of the cap 210 by the user. According to one aspect of the present invention, the cap unit 210 can have a diameter of about 4.0 cm (diameter) x about 0.75 cm (thickness), as defined by Definitive Design Inc. (Langhorne, PA). . According to one aspect of the present invention, the cap unit 210 can be made disposable so that the cap can be discarded and replaced with a new cap unit 210 after the material has been dispensed from the cap 210. Alternatively, the pad 14 can be configured to be replaced without the need for a new cap unit 210. In any case, additional material to be delivered can be provided without replacing the transducer coupler 201. Of course, the device 300 (FIG. 9) can be designed such that the transducer coupler 201 (FIG. 10) can be periodically replaced or the entire assembly 300 can be designed as a single non-reusable device. Is possible.

  Referring now to FIG. 12, the cap unit 210 may be comprised of an outer snap ring 230 and an inner snap ring 220 housed inside the outer snap ring 230. According to one aspect of the invention, the inner snap ring 220 can substantially secure the absorbent pad 14 in place. Referring now to FIGS. 13 and 14, the inner snap ring 220 can include at least one inner connector tab or bayonet 222 and at least one outer connector tab 221. The outer snap ring 230 may include at least one connector groove 211 into which the outer connector tab 221 of the inner snap ring 220 can be inserted to threadably couple the inner snap ring 220 to the outer snap ring 220. it can. In order to allow a tight connection when screwing the cap unit 210 to the transducer coupler 201, the inner connector tab 222 can be fitted into the transducer cap connector groove 203 (FIG. 10). According to one aspect of the present invention, the connection between the cap unit 210 and the transducer coupler 201 can form a sonic connection between the absorbent pad 14 and the transducer coupler 201. In this configuration, the absorbent pad 14 can be secured adjacent to or substantially adjacent to the transducer coupler 201.

  Referring now to FIGS. 15 and 16, a transdermal delivery device or assembly 300 according to one embodiment of the present invention is shown. The delivery device can include a transducer coupler 201 having a transducer housing 202 in which at least one ultrasonic transducer 18 (not shown) or transducer 18 array can be disposed. According to one embodiment of the present invention, the transducer array can be 2 × 2 rows. The delivery device can further include a cap unit or patch cap 210 that houses an absorbent pad 14 (shown in FIG. 32A) containing at least one substance to be delivered. The acoustic membrane 11 (not shown) may be configured as part of the cap unit 210 so as to cover the absorbent pad 14 on the side disposed in contact with the transducer coupler 201, or the cap unit 210 It may be affixed to. According to one aspect of the present invention, the sonic membrane 11 is commercially available as Saran®, including but not necessarily limited to model number Dow BLF-2014 available from Dow Chemical Company (Midland, Mississippi). It may be composed of a polyvinylidene chloride plastic film, such as a film that has been made. According to one embodiment of the present invention, the sonic membrane 11 can have a diameter of about 4.0 cm and a thickness of about 50 μm. According to one aspect of the present invention, the sonic membrane 11 includes, but is not limited to, Mylar®, a polyester film, for example, model number M34 available from DuPont Teijin Film Division (Wilmington, Del.). ) Can be composed of film. According to one aspect of the present invention, the acoustic membrane can have an approximate dimension of 4.0 cm (diameter) × 13 μm (thickness). The release film 12 (not shown) is part of the cap unit 210 to cover the side of the absorbent pad 14 that is placed against a substance delivery subject, such as the subject's skin, before removing it. Can be configured. Once the release film 12 is removed, the absorbent pad 14 containing at least one substance can be exposed to be fixed adjacent to 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) below the cap 210 such that the semi-permeable membrane 13 is in functional proximity of the subject. be able to. Semi-permeable membrane 13 includes, but is not necessarily limited to, an ethylene / methacrylic acid copolymer (such as a film marketed as Surlyn® available from DuPont (Wilmington, Del.)). Or any other suitable material. According to one aspect of the present invention, the semipermeable membrane 13 can have an approximate dimension of 4.0 cm (width) × 4.0 cm (length) × 50 μm (thickness).

  The transdermal delivery device can be configured such that the cap unit 210 and the transducer coupler 201 can be press fit or snapped together to form the transdermal delivery device or assembly 300. A press fit or snap fit, or other suitable connection coupling system or device may be used to connect the cap unit 210 and the transducer coupler 201.

  A lead or cable 204 can be used to connect the transducer 18 (not shown) to the power supply and / or control unit 400 (shown in FIG. 32G) and can be derived from the transducer coupler 201. .

  A strap 250 (not shown) can be used to secure the transdermal delivery device 300 to the subject's body (shown in FIGS. 32E and 32F). The pressure generated by the connection of the strap 250 to the subject can establish a functional interface between the absorbent pad 14 (FIG. 32A) and the surface of the subject. The pressure generated by the connection of the strap 250 to the subject can be used to establish a sonic connection or interface between the absorbent pad 14 and the surface of the subject. The pressure generated by the connection of the strap 250 substantially prevents leakage of material from the underside of the cap 210 and substantially prevents contamination of the material being delivered to the surface of the subject. And the surface of the subject can be established.

  The pressure induced by inserting or pushing the cap unit 210 into the transducer coupler 201 can establish a sonic connection or interface between the transducer coupler 201 and the sonic membrane 11 of the cap unit 210. The pressure induced by inserting or pushing the cap unit 210 into the transducer coupler 201 can establish a sonic connection or interface between the sonic membrane 11 and the absorbent pad 14.

  Alternatively, according to one aspect of the present invention, the transducer coupler 201 can be snapped or press fitted to the cap unit 210 as well.

  Referring now to FIGS. 17 and 18, there is shown a transducer coupler 201 suitable for use with the present invention. The transducer coupler 201 can further include a housing 202 having at least one transducer cap connector groove 203. The transducer coupler can further include a sonic faceplate 205 designed to form a sonic interface with the cap unit 210 (FIG. 15). According to one aspect of the present invention, transducer coupler 201 may be about 4.0 cm in diameter and about 1.0 cm in thickness and manufactured by Sonic Systems Inc. (Newtown, Pa.). . The housing 202 can be composed of any suitable material. In accordance with one aspect of the present invention, the housing 202 may be composed of plastic components, for example, epoxy sold as Eccobond® 45LV and catalyst 15LV available from Emerson & Cumming (Billerca, Mass.). The sonic faceplate 205 can be composed of any sonic compatible material, such as, for example, a stainless steel plate approximately 4.0 cm (diameter) × 1.0 mm (thickness) available from Sonic Systems Inc. (Newtown, Pa.). .

  Referring now to FIGS. 19-22, the cap unit 210 (shown in FIGS. 32A and 32B) has an outer snap ring 230 (shown in FIGS. 21 and 22) and an outer side (as shown in FIG. 32C). It can be comprised of an inner snap ring 220 (shown in FIGS. 19 and 20) that is substantially secured within the snap ring 230. In accordance with one aspect of the present invention, when the inner snap ring 220 is substantially secured within the outer snap ring 230, the inner snap ring 220 substantially replaces the absorbent pad 14 (shown in FIG. 32A). ) Can be fixed in place.

  The cap unit 210 can be composed of any suitable material. According to one aspect of the invention, it may have about 4.0 cm (diameter) x about 0.75 cm (thickness) as defined by Definitive Design (Langhorne, PA). According to one aspect of the invention, the cap unit 210 is made disposable so that after the material has been dispensed from the cap unit 210, the cap unit can be discarded and replaced with a new cap unit 210. be able to. Alternatively, the pad 14 can be configured to be replaced without the need for a new cap unit 210. In any case, additional material to be delivered can be provided without replacing the transducer coupler 201. Of course, the device 300 (FIG. 15) can be designed such that the transducer coupler 201 (FIG. 17) can be periodically replaced or the entire assembly 300 can be designed as a single non-reusable device. Is possible.

  The cap unit 210 can include an absorbent pad 14 (FIG. 32A) containing at least one substance to be delivered. According to one aspect of the present invention, absorbent pad 14 is comprised of a cellulose pad comprising an ethylene vinyl acetate based synthetic latex-containing wood pulp such as Vicell # 6009 available from Buckeye Absorbent Products (Memphis, TN). sell. According to one aspect of the present invention, the absorbent pad 14 can have a diameter of about 4.0 cm and a thickness of about 0.92 mm. The cap unit 210 is in contact with the subject's skin and substantially prevents the entry of air or contaminants under or into the device and the leakage or contamination of the material deposited on the subject's skin by the transdermal delivery device. It can further include an adhesive or sealing ring 213 (not shown) suitable for forming a preventing seal. In accordance with one aspect of the present invention, the adhesive ring 213 can be constructed of foam tape model number 3M 9772-L, which is a back adhesive polyvinyl chloride available from 3M Company (St. Paul, Minn.). According to one aspect of the present invention, the adhesive ring 213 can be composed of model number 3M 9773 foam tape, which is a back adhesive polyolefin film. According to one aspect of the present invention, the adhesive ring 213 can have an approximate dimension of an internal opening of 3.75 cm in diameter and a ring dimension of 0.25 cm × 1.0 mm (thickness).

  Referring now also to FIGS. 19 and 20, the inner snap ring 220 can include at least one inner connector tab or bayonet 222 and at least one outer connector tab 221. Referring now to FIGS. 21 and 22, the outer snap ring 230 snaps the inner snap ring 220 into place, or press fits, to make the inner snap ring 220 substantially the outer snap ring 230. At least one connector groove 211 can be included into which the outer connector tab 221 of the inner snap ring 220 can be inserted for securing within. Of course, any suitable means that allows the inner snap ring 220 to be substantially secured with a snap fit within the outer snap ring 230 may be utilized. Referring also 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 a snap-fit or press-fit connection to form a cap unit 210. (Shown in FIGS. 32A and 32B). When coupling the cap unit 210 to the transducer coupler 201, the inner connector tab 222 can be fitted into the transducer cap connector groove 203 to allow a tight connection. According to one aspect of the present invention, the connection between the cap unit 210 and the transducer coupler 201 can form a sonic connection between the absorbent pad 14 (FIG. 32A) and the transducer coupler 201. In such a configuration, the absorbent pad 14 can be secured adjacent or substantially adjacent to the transducer coupler 201 (shown in FIGS. 32A-32C).

  Referring now to FIGS. 24A-31, achievable results according to one embodiment of the invention are shown.

  Referring now to FIGS. 32A-32C, a transdermal delivery assembly according to one embodiment of the present invention is shown.

  Referring now to FIGS. 32D and 32E, achievable results according to one embodiment of the present invention are shown.

  Referring now to FIG. 32E, a desktop transdermal delivery system according to one embodiment of the present invention is shown.

  Referring now to FIG. 32F, a belt-mounted transdermal delivery system according to one embodiment of the present invention is shown.

  Although the present invention has been described in detail so far, there are several variations on the design and function of the device, but it is understood that such design and function variations are included in this disclosure. The merchant will understand. Further, while the invention has been disclosed with some specificity, the preferred form of the disclosure has been made by way of example and without departing from the spirit and scope of the invention as claimed herein. It will be understood that many changes may be made in the details of the structure, combination and construction of the invention.

It is a figure which shows the transdermal patch with an ultrasonic generator which a patient wears, such as arrange | positioning at a patient's arm. It is explanatory drawing of the structure of human skin. FIG. 6 shows a transdermal patch with the transducer on the outside of the patch. It is a figure which shows the transdermal patch comprised by employ | adopting a gasket or a sealing material around the edge of a patch. It is a figure which shows the ultrasonic signal which changes alternately from a sawtooth waveform to a square wave. FIG. 6 shows a transdermal patch with a transducer or transducer array embedded directly in the patch. FIG. 6 is a diagram showing a transdermal patch in which a semi-permeable membrane disposed on the lower side of a patch serves to provide a valve function by administration of an ultrasonic wave transmitted through the patch. FIG. 6 illustrates a patch according to an aspect of the present invention. 1 illustrates a transdermal delivery device according to one aspect of the present invention. FIG. FIG. 9 illustrates a transducer coupler according to an embodiment of the present invention suitable for use with the device of FIG. 9, wherein the transducer coupler is configured to couple to a cap unit containing at least one substance to be delivered. FIG. FIG. 11 illustrates a cap unit configured to couple to the transducer coupler of FIG. FIG. 12 is an internal view of the cap unit shown in FIG. FIG. 12 shows an inner snap ring of the cap unit of FIG. FIG. 12 is a view showing an outer snap ring of the cap unit of FIG. FIG. 6 shows a top view of a transdermal delivery assembly or device according to one aspect of the present invention. FIG. 16 is a bottom view of the transdermal delivery assembly of FIG. FIG. 16 illustrates a top view of a transducer coupler suitable for use with the assembly of FIG. 15 configured to couple to a cap unit containing at least one substance to be delivered. . FIG. 18 shows a bottom view of the transducer coupler of FIG. It is a figure which shows the upper side figure of the inner side ring of a cap unit. FIG. 21 is a diagram showing a bottom view of the inner ring of FIG. It is a diagram showing a top view of the outer ring of the cap unit FIG. 22 is a diagram showing a bottom view of the outer ring of FIG. FIG. 16 is an exploded view of the assembly of FIG. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. 1 illustrates a transdermal delivery device according to one aspect of the present invention. FIG. 1 illustrates a transdermal delivery device according to one aspect of the present invention. FIG. 1 illustrates a transdermal delivery device according to one aspect of the present invention. FIG. FIG. 4 illustrates achievable results according to one aspect of the present invention. FIG. 4 illustrates achievable results according to one aspect of the present invention. 1 illustrates a tabletop transdermal delivery system according to one aspect of the present invention. FIG. 1 illustrates a belt-mounted transdermal delivery system according to one aspect of the present invention. FIG.

Claims (20)

A system suitable for immobilizing substantially adjacent to the surface of the subject so as to deliver at least one substance into the subject from the surface of the subject;
At least one opening for receiving at least one ultrasonic transmission, wherein the at least one substance is releasably secured substantially adjacent to the at least one opening; and
A sonic member disposed relative to the at least one aperture to transmit the at least one transmission to the at least one substance so as to deliver the at least one substance from the surface of the subject; Including system.   Further comprising at least one ultrasonic transducer suitable for placement substantially adjacent to the opening to emit ultrasonic transmission from the opening, wherein a replaceable cap includes the substance, the opening and the sonic member. The system according to claim 1.   The system of claim 2, wherein the transducer includes a plurality of transducer elements.   3. The system of claim 2, wherein the replaceable cap further includes a pad that substantially contains the substance and is disposed substantially between the opening and the sonic member.   2. The system according to claim 1, wherein the sonic member includes at least one material selected from the group consisting of saran and mylar.   5. The system of claim 4, wherein the pad comprises at least one material selected from the group consisting of cotton, cellulose and nylon.   5. The system of claim 4, further comprising a housing configured to define the opening, couple to the sonic member, and receive the pad in a snap-in manner.   A half positioned substantially adjacent to the pad and forming an ultrasonically activated normally closed valve function to control delivery of the at least one substance from the surface of the subject. The system of claim 4 further comprising a transmissive film.   The system of claim 2, wherein when the transducer is activated, the substance is transmitted through the acoustic wave member and accumulates on the surface.   The system of claim 2, wherein the transducer and cap are attachable to the surface.   The system of claim 2, wherein the system is at least partially secured to the surface.   The system of claim 2, further comprising an ultrasound transducer driver for selectively activating the transducer according to at least one dosing requirement.   The system of claim 2, wherein the ultrasonic transmission comprises a signal of about 20 to about 30 kHz, about 125 to about 225 mW / cm.   The system of claim 13, wherein the cap is removably coupled to the transducer.   15. The system of claim 14, wherein the cap is screwed or snapped to the transducer.   The system of claim 2, wherein the transducer includes a groove to facilitate securing the cap to the transducer.   The system of claim 2, wherein the cap further includes inner and outer rings coupled to each other, the inner ring including a protrusion suitable for connection with the groove in the transducer.   3. The system of claim 2, wherein the cap substantially contains the material, and the cap compresses the pad against the transducer. A system suitable for immobilizing substantially adjacent to the surface of the subject so as to deliver at least one substance into the subject from the surface of the subject;
A transducer housing;
A plurality of ultrasonic emitters in the transducer housing;
A cap defining at least one opening for receiving radiation from said element;
A pad for releasably securing the at least one substance substantially adjacent to the at least one opening in the cap;
A sonic member disposed relative to the at least one opening to transmit the radiation to the at least one pad to effect the delivery of the at least one substance from the surface of the subject. system.   20. The system of claim 19, wherein when the cap is secured to the transducer and the system is secured to the surface, the material is secured by the pad substantially adjacent to the surface.

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