JP2006508763A - Wearable portable sonicator for inducing release of bioactive compounds from internal organs - Google Patents

Abstract

The present invention relates to a portable device for transmitting sonic energy from an ultrasonic generator through the outer surface of a patient's skin for the purpose of enhancing the release of a biofunctional compound from a target organ for the treatment of disease or trauma. It is. In particular, the present invention is a means to enhance the treatment of diabetes by releasing insulin from the patient's pancreas. Making the portable device programmable with respect to sound frequency, intensity and time adjusts the amount of insulin that can be induced to be released in response to sonic transmission from the patient's pancreas. The device can be programmed for continuous sonic or intermittent transmission as required. The device is primarily intended for patients with type 2 diabetes who produce insulin internally, but not necessarily in the amount or time required for effective biological function. In such cases, the present invention through the use of sonic transmission can be used to artificially induce the proper release of insulin from the pancreas of a diabetic patient with or without the use of additional agents. .

Description

  The present invention augments insulin from the pancreas of diabetic patients by inducing the pancreas to release a greater amount of insulin in response to sonic transmission administered from the skin through a device attached to the exterior of the body The present invention relates to a portable guidance system. In particular, sonic energy delivered by a portable self-contained programmable ultrasound transducer located in the patient's pancreas region causes the spleen of the diabetic patient to release insulin in response to activation of ultrasound transmission.

  The present invention relates to a portable programmable ultrasound device worn by a patient to cover a pancreatic region for the purpose of inducing the pancreas to release insulin on demand in response to acoustic transmission. In addition, the portable sonicator is programmed to release a variable amount of insulin over time by applying sonic energy at different times, with or without the accompanying treatment of other medicinal compounds. Can be Of the methods that release insulin continuously (continuous release) and those that release insulin intermittently (intermittent release), this is considered to be more suitable for the insulin management plan and treatment for specific diabetic patients. It can be programmed to deliver ultrasound transmission that induces the pancreas of diabetic patients to release insulin.

  In the prior art, some medicinal compounds have been identified as being suitable for the treatment of type 2 diabetes as insulin promoters. Basically, these drugs are used to enhance the ability of type 2 diabetics to make better use of the insulin they produce. Some of the most needed drugs are currently administered in injection or oral dosage forms.

  Recent studies conducted on ultrasound-based enclosures (Langer, Edwards, Kost-MIT-1995) have required the use of ultrasound devices by applying ultrasound to transdermal delivery devices and patches. This suggests that the penetration and / or absorption of certain low molecular weight drugs through the cortex, which is normally expected to have low skin penetration, can be enhanced. When low frequencies are applied to transdermal patches for certain drugs, sonophoresis, the use of ultrasonic energy to enhance the bioabsorption of large protein molecules or large molecule drugs through the outer layer of the skin, is possible. Patent Document 1 describes a clinical device for inducing enhanced drug delivery via sonication.

  Although this patent describes a method for enhancing transdermal drug delivery utilizing low frequency ultrasound for specific drug delivery, the method is useful in clinical ultrasound delivery environments. Requires the use of. Furthermore, measurable amounts of delivery time using these methods range from 10 minutes to 24 hours. In this method, the use of an ultrasonic transdermal drug delivery process is less preferred than simple injection in terms of patient administration. This method is undesirable because it requires the patient to remain on the treatment table while visiting the clinical environment and delivering the drug using sonication. This method damages the skin because it continuously treats the same area of the skin.

  Ultrasound has also been used to improve the permeability of skin and synthetic membranes to drugs and other molecules. Ultrasound was defined as a mechanical pressure wave with a frequency exceeding 20 kHz (Non-patent Document 1). Ultrasonic waves are generated by vibrating a piezoelectric crystal or other electromechanical element by passing an alternating current through a substance (Non-Patent Document 2). The use of ultrasound to increase skin permeability to drug molecules has been termed sonophoresis, or phonophoresis.

  Patent Document 2 describes the topical application of a drug in a coupling agent for the treatment of herpes virus infection and Demidox tick infection. The medicine is rubbed into the affected area by ultrasonic waves to penetrate the skin. Patent document 3 similarly describes the topical application of zinc sulfate and ascorbic acid in a coupling agent for the treatment of acne.

  Patent Document 4 uses an ultrasonic wave having a frequency range of 20 kHz to 10 MHz and an intensity range of 0 to 3 W / cm 2 to enhance and control the injection of molecules with low skin permeability. A method is disclosed. The molecule is introduced into the coupling agent or added through a transdermal patch. Kost et al. Further teach that time, frequency and power parameters can be optimized to accommodate individual situations and differences in permeability of different molecules and different skins. Patent Document 5 also discloses transbuccal drug administration using ultrasound.

  Patent Document 6 discloses that a specific frequency (that is, a frequency exceeding 10 MHz) is used to increase the penetration rate of a drug through the human skin into the body. When the frequency exceeds 10 MHz, the permeability of the skin improves beyond the level already mentioned. It has been argued that chemical penetration enhancers and / or iontophoresis in combination with sonication can also enhance the delivery of drugs through the skin to the body.

  Patent Document 7 shows local application of a drug by implanting a drug-containing container in the vicinity of a body tissue to be treated, and then applying ultrasound to guide the drug from the container to the body tissue. This method has the disadvantage of requiring surgical implantation of the drug container and non-invasive techniques are preferred. Patent Document 8 discloses a kit for delivering an external drug including a drug-containing layer, and an ultrasonic oscillator for releasing the drug to be taken up through the surface of the skin. Patent Document 9 describes an application kit in which a drug layer and an ultrasonic transducer are arranged in a housing. The transducer may be battery powered. The ultrasound can move the drug from the device to the skin and then change the ultrasound energy to control the rate of administration through the skin.

  Other references teaching the use of ultrasound for drug delivery through the skin include Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7, and Non-patent document 8 is cited.

  Other methods have been described to increase skin permeability to drugs, such as ultrasound or iontophoresis. Iontophoresis involves the local delivery of an ionized form of drug or non-ionized drug carried by the application of an external electric field and water flow associated with ion transport (electroosmosis). Although improved permeability by iontophoresis has been achieved, controlled drug delivery and irreversible skin damage are challenges associated with this technique.

  Thus, the use of ultrasound for drug delivery is known, but the results are significantly disappointing in that the improvement in permeability is relatively small. There is no consensus on the effect of ultrasound to enhance drug flow to the skin. Some studies have reported the success of iontophoresis (Non-patent document 9, Non-patent document 10, Non-patent document 11, Non-patent document 12, Non-patent document 13, and Non-patent document 3). Thus, a negative result is obtained (Non-patent Document 14, Non-Patent Document 15, and Non-Patent Document 16). The system employing rodent skin showed the most promising results, and the system employing human skin overall showed disappointing results. Since rodent skin is well known to those skilled in the art to be much more permeable than human skin, the above results are consistent with ions applied for transdermal delivery and / or monitoring through human skin. It does not teach those skilled in the art how to effectively use electrophoresis.

  Applicants believe that other uses for ultrasound aimed at medical purposes are to induce the pancreas to release insulin in response to ultrasound signals, with or without the addition of drugs. It is suggested. Inducing the pancreas to release insulin on demand by altering the parameters of the ultrasound, creating a resonance effect in the patient's body, essentially massaging the pancreas over time Can do. Applicants theorize the control of sonic frequency, intensity, and exposure time to produce an effect on noninvasive pancreatic induction that affects on-demand insulin release. All three of these parameters can be combined and modulated at the same time to enhance the effectiveness or efficiency of ultrasound associated with improving the biomolecule flow rate of insulin from the patient's pancreas.

In order to induce a focused harmonic transmission to a specific organ in the body for the purpose of producing a mild harmony effect internally in the patient's body, the applicant of the present application is described in Patent Document 10, Patent Document 11 And a small transducer with a design similar to that proposed in Patent Document 12 was found. The Applicant further supports theoretically that focused ultrasound transmission can be used to guide the organ to release bioactive compounds that support the fight against disease. One such application is to induce the pancreas to release insulin on demand in response to ultrasound transmission. Other uses of the invention can include the release of antibodies, endorphins or enzymes from other organs, tissues, or even skeletal structures that fight other diseases or conditions.
U.S. Pat.No. 5,947,921 (Kost et al) H. Lutz et al., Manual of Ultrasound 3-12 (1984) R. Brucks et al., 6 Pharm. Res. 697 (1989) U.S. Pat.No. 4,309,989 (Fahim) U.S. Pat.No. 4,372,296 (Fahim) U.S. Pat.No. 4,767,402 (Kost et al) U.S. Pat.No. 4,948,587 (Kost et al) U.S. Pat.No. 5,115,805 (Bommannan et al.) U.S. Pat.No. 5,016,615 (Driller et al.) U.S. Pat.No. 4,821,740 (Tachibana et al.) U.S. Pat.No. 5,007,438 (Tachibana et al.) D. Bommannan et al., 9 Pharmaceutical Res. 559 (1992) D. Bommannan et al., 9 Pharmaceutical Res. 1043 (1992) K. Tachibana, 9 Pharmaceutical Res. 952 (1992) P. Tyle & P. Agrawala, 6 Pharmaceutical Res. 335 (1989) H. Benson et al., 8 Pharmaceutical Res. 1991 D. Levy et al., 83 J. Clin. Invest. 2074 (1989) J. Davick et al., 68 Phys. Ther. 1672 (1988) J. Griffin et al., 47 Phys. Ther. 594 (1967) J. Griffin & J. Touchstone, 42 Am. J. Phys. Med. 77 (1963) J. Griffin et al., 44 Am. J. Phys. Med. 20 (1965) (D. Levy et al., 83J. Clin. Invest. 2074) H. Benson et al., 69 Phys. Ther. 113 (1988) J. McElnay et al., 20 Br. J, Clin. Pharmacol. 4221 (1985) H. Pratzel et al., 13 J. Pheumatol. 1122 (1986) U.S. Pat.No. 5,729,077 (Newnham) U.S. Pat.No. 5,276,657 (Newnham) U.S. Pat.No. 4,999,819 (Newnham)

  Accordingly, an object of the present invention is a device for enhancing or increasing insulin release in diabetic patients through the use of ultrasound, which is self-powered, portable or wearable by a patient and programmable Is to provide.

  The present invention is placed in direct contact with the skin, ideally for diabetic patients, to enhance and control insulin release in type 2 diabetic patients with or without the use of concomitant drugs. A wearable or portable programmable sonic applicator placed directly over the pancreas. The device is placed directly on the patient's skin and held in place with an adhesive band or body strap. When activated by an internal timing circuit, the sonic applicator generates ultrasonic vibrations or transmissions through the patient's body. Although the exact mechanism by which ultrasound functions to increase insulin release is not understood, the ultrasonic and vibrational sonic energy induced in the patient's pancreas is generated from the pancreas and the patient's blood flow. It is thought to increase the release of insulin leading to.

  The sonic applicator is provided with a control circuit for adjusting the timing, frequency and intensity of sonic energy applied to the patient's skin. By adding a continuous ultrasonic or vibration mode, the control circuit can be set so that the ultrasonic effects can be managed continuously. Alternatively, the device control circuit can be set to pulsate with various on-off cycles for the entire processing time. The duration of the cycle for the day and its intervals can be programmed to provide intermittent administration of the patient's released insulin.

  Since the sound wave applying device of the present invention is wearable, it is portable and can be attached to a patient by an adhesive band or a strap. The sonic applicator includes a unique power battery. When power is reduced, the battery can be replaced or charged if a rechargeable battery is used. Combined with the ultrasound applicator worn by the patient, several drug delivery benefits are provided.

  1) The sonic applicator can provide a non-invasive insulin delivery means that relies primarily on inducing the patient's pancreas to release the required insulin dose on demand.

  2) The sonic applicator can guide the patient's pancreas to release the required insulin dose with or without the use of an associated drug. As such, it reduces the need to rely on drugs and allows patients to avoid complications associated with long-term use of the chemical formulation in the treatment of diabetes.

  3) The system can be programmed to provide continuous drug delivery or intermittent timed drug delivery at a specific drug amount to increase flexibility and control over the specific patient's dosing needs. Conventional drug delivery systems are steady-release devices that provide a one-size, full treatment response that is not suitable for drug treatment of all patients.

  Thus, the main object of the present invention is a portable programmable device that uses ultrasound to induce and control the release of internally generated insulin from the pancreas of diabetic patients.

  Another object of the present invention is a method for non-invasive delivery of insulin by the use of ultrasound administered through the skin and directed to the pancreas of a diabetic patient, wherein only sonic therapy is applied and is used for the treatment of diabetes. This is a method that does not use drugs.

  Another object of the present invention is a method for non-invasive delivery of insulin by the use of ultrasound administered through the skin and directed at the pancreas of a diabetic patient, in combination with an appropriate therapeutic agent for diabetes. This is a method in which sonic therapy is performed.

  These and other objects of the present invention are to apply various ultrasonic frequencies, intensities, amplitudes and / or phase modulations to control the magnitude of transdermal flow to treat insulin from the pancreas of diabetic patients. Can be accomplished by achieving targeted release.

  One aspect of programmability and flow control is treatment for individual patients (for example, patients with different stages of disease, elderly patients, young patients, adolescent patients, or patients of different genders). Is the ability to optimize delivery.

  Another aspect is to optimize insulin release delivery in combination with appropriate chemotherapy. The molecular structure of each biologically active molecule is different and responds differently to ultrasound. By controlling the frequency, intensity, concentration, timing of delivery, and associated drug therapy, the effect of each drug type used with sonic therapy in diabetes treatment can be optimized.

  A preferred embodiment of the present invention is the use of a device for insulin therapy by inducing insulin delivery from insulin from the induced pancreas. However, since the Applicant recognizes that this same technique can be used to induce the release of other life-saving compositions from other organs, it does not want to limit the present invention only to the treatment of diabetes. . In addition, when pH or enzymes in the blood or liver or other organs change in response to ultrasound, other treatments for various diseases or illnesses can be performed by allowing ultrasound therapy to target the activity of the organ system or blood. be able to.

  Another embodiment of the invention is to achieve organ stimulation and activation using phase modulation, alternating waveform and frequency modulation.

  Another aspect of the present invention is the use of ultrasound in combination with agents such as iontophoresis, electroporation, alopecia, or diabetics to release on-demand insulin from the diabetic patient's own pancreas or endocrine system. Is to encourage.

  Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will be understood by those skilled in the art upon reading the following description or practice of the invention. You can learn by doing.

  FIG. 1 shows the present invention comprising a sonication device (1) ideally worn on a patient's belt (4). Alternatively, the sonic applicator device (1) can be attached to the patient by a strap and in fact can be placed anywhere on the body that is convenient for the patient to control the function of the device. Another position is shown in FIG. 2 and is worn on the arm. However, FIG. 1 shows that it is preferably placed on the patient's waist for treatment from the abdomen. This device includes a rechargeable battery to be carried by the patient, worn by the patient, and to ensure mobility of treatment. This ensures patient compliance with drug therapy since there is little to do for the patient other than keeping the system in place.

  The transducer device (2) is ideally worn on the skin surface (6) of the patient (5) on the target organ, such as the pancreas or liver in the case of diabetes treatment.

  The power to the sonic applicator (1) is provided by a battery (not shown) that is ideally rechargeable and can be placed in the strap (4) itself.

  Alternatively, the power source can be included within the sonic delivery device (1) itself or provided from an external delivery source. To be completely portable, the unit is replaceable and ideally includes a rechargeable battery system within it. Alternatively, an external battery pack may be worn and connected to the applying device. Applicants assume that a preferred system has a battery housed within the strap (4) of the device.

  A single transducer or array of ultrasonic transducers controlled by a frequency generator and a sonic driver circuit in the sonic applicator device (1) generates a sonic transmission. The circuit controls the device setup and activation order.

  The lead (3) connects the ultrasonic transducer assembly (2) to the sonic applicator device. The ultrasonic transducer assembly (2) may be any suitable device suitable for transmitting sound waves or transmitting ultrasonic waves through the patient's body.

  Coupling agent compounds such as hydrogels containing water insoluble drugs such as silica gel can be used under the transducer to help maintain contact with the skin and maintain the integrity of the ultrasound signal.

Transducer Element Design FIG. 4 is a diagram illustrating the design of a cymbal ultrasonic transducer (40) which is a preferred embodiment of the transducer element of the present invention. From FIG. 4, the cymbal transducer (40) is based on a piezoelectric disk (41) such as PZT4 (Piezokinetics (Bellefonte, PA)) connected to two metal caps (42), preferably composed of titanium foil. . FIG. 4 shows that a hollow space (43) exists between the piezoelectric disk (41) and the terminal cap (42).

  The terminal cap (42) is connected to the piezoelectric disk (41) with a non-conductive adhesive (44) to form the adhesive layer structure of the transducer (40). The cymbal transducer provides a thin and compact structure that is more suitable for portable ultrasound drug delivery devices. Furthermore, the conversion efficiency of electric power into acoustic radiation power is increased. Applicants also choose this transducer design because it can be battery powered.

  Ideally, a low frequency ultrasonic wave of 20 to 100 kHz using an alternating waveform (saw waveform to square wave) is used for a cymbal transducer capable of battery-powered ultrasonic transmission. A transducer array is arranged for each transducer element that avoids effects on a single skin transmission site and provides versatility in ultrasonic frequency and intensity.

  FIG. 5 shows that the cymbal transducer allows a compact and small size for the transducer element of the present invention. Sizing of the transducer was obtained with only 0.5 inch diameter. In the present invention, a small size transducer was required to keep the transducer within the dimensions of the transdermal patch. In addition, the small size allows the weight of the transducer to be reduced, further enhancing the portability of the present invention. The transducer element (50) is a cymbal structure that is attached to the power cable (51). The transducer element (50) is used to avoid a short circuit between two metal caps (42) (Figure 4) and is a polymer ideally composed of uralite resin that provides acoustic coupling for acoustic transmission Covered by the casing (52).

  The cymbal transducer design offers several important advantages over the prior art.

  -Compact structure and small surface area.

  ・ Low resonance frequency and high sound pressure and sound intensity.

  -Because the efficiency is high, the driving force required by the system is small.

  In order to avoid increasing the cavitation threshold, i.e. the intensity required to generate air bubbles in the stratum corneum of the patient's skin tissue, the use of low resonance frequencies is required. Since the cavitation threshold is directly proportional to frequency, selecting the low resonant frequency of the transducer can lower the sound pressure applied to the surface of the skin, affecting transdermal drug delivery.

Blueprint 6 of the transducer array is a diagram showing a sequence (60) comprising a plurality of cymbals elements (61) which is accommodated in or is arranged in a suitable pattern on the lower structure, or a polymer casing (62) in . The cymbal elements (61) are connected in parallel by a series of electrical connections (63). The array (60) is then sealed with a polymer potting material (62), preferably composed of uralite. The array allows for portable, battery-powered ultrasound transmission with sufficient power to affect drug delivery by a transdermal patch.

  In a preferred embodiment of the invention, the transducers work in series and transmit collectively. Alternative designs can activate each element of the transducer array in turn for each transducer, and can include transducers that can vary in waveform, frequency, amplitude, and period of operation between each transducer element It is. This has the effect of releasing the skin transmission site from continuous ultrasonic stress and maximizes the variability of ultrasonic skin transmission energy manipulation.

  The transducer array shown in FIG. 6 provides a means of extending the drug delivery site along the skin surface by delivering ultrasonic transmission from a plurality of transducer elements (61) acting on the skin. Transducer elements (61) can be activated simultaneously or sequentially to transmit ultrasound to the patch and to multiple sites on the skin surface. Furthermore, the frequency, intensity and waveform can be varied for each transducer element (61) in the row (60). This change has the effect of increasing efficiency, improving power utilization, and extending the battery life of the portable system. Furthermore, the alternating transducer element (61) helps to prevent over-exposure of the skin to excessive frequency ultrasound.

  Two or more transducer rows, particularly cymbals, are useful for introducing drugs to multiple skin transmission sites. Furthermore, the standard advantages of the transducer arrangement are to reduce skin damage and increase efficiency and transmitted sound intensity. By alternating the transducer activation sequence, it is possible to avoid effects on the skin and to ensure an extended useful life of the skin transmission site.

  The use of transducer rows, particularly cymbal transducers, in portable wearable ultrasonic drug delivery devices increases power utilization efficiency and helps to avoid damaging effects of excessive cavitation on the skin. The arrangement allows long-term battery delivery that provides sufficient power to allow the device to function for several days between filling or replacement cycles. Ideally, the use of rechargeable battery delivery with a battery included in the strap of the device will ensure complete patient mobility and ensure power delivery to the device over several months of repeated use.

  FIG. 2 is a diagram showing a control environment of a sound wave applying device (1) designed for controlling insulin therapy using ultrasonic waves. These controls allow the device to be programmed to deliver ultrasound to the patient's body at defined intervals.

  The keypad (10) provides control functions that can be set by the patient or medical professional. The current embodiment of the sonic applicator unit (1) has a keypad (10) that provides several functions.

  The enter key (15) is an on / off control button. Upon activation, the stored battery power is sent to other control elements and sonic applicator elements. It also allows the operator to enter functions and commands displayed on the display (16).

  Diabetic patients require a basic delivery schedule for the release of insulin. Basalsky 1 (1) is active over a certain period of time so that the device can transmit an ultrasound signal that stimulates the patient's pancreas organ under the skin surface and releases a certain amount of insulin over a period of time. Allows the operator to configure the device to

  Diabetic patients may require a massive instantaneous delivery schedule for insulin release, especially during mealtimes or intense physical activity. Borasky (12) is active over a period of time so that the device can transmit an ultrasound signal that stimulates the patient's pancreas organ under the skin surface and generally releases a specific amount of insulin in a short period of time. Allow the operator to configure the device to

  Control (+) (13) allows the operator to scroll up towards the desired selection based on the desired time interval or the corresponding dose that is desired to be released by ultrasonic stimulation.

  Control (-) (14) allows the operator to scroll down towards the desired selection based on the desired time interval or the corresponding dose that it is desired to release by ultrasonic stimulation.

  Once the setting is obtained, it is input to the electronic logic circuit of the device via the enter key (15). The display (16) shows the selection and device status.

  If the device encounters an inappropriate input, or if its self-diagnostic circuit indicates a problem, an audible alarm is emitted from the speaker (17) and a red indicator light is lit (18). The display (16) then becomes a message center that identifies the problem and recommends a series of actions.

  A preferred embodiment of the sonication device maintains a memory of all settings, self-diagnosis reports and activation order. This information is downloaded to the medical professional via a modem, which can then access the patient's medication history. This data allows medical professionals to retune the device to meet the specific patient's insulin treatment needs.

  The device can be set up by a medical professional or used by the patient himself in an insulin treatment plan. Alternatively, the device can receive a signal from the glucose sensor and activate it to stimulate the pancreas to the extent necessary to maintain an appropriate insulin treatment level. As such, this closed loop system will function as an artificial pancreas.

  Control of the device activates a sonic driver circuit in the device, which is an oscillating circuit capable of providing the appropriate ultrasonic frequency and intensity level to the transducer to generate the appropriate sonic transmission. is there. Ideally, the frequency and intensity generator settings are preset for a particular frequency and intensity of sonic energy delivery. The control setting determines the periodicity of ultrasonic application. With this setting, for example, the generation of 100 ultrasonic pulses per second duration is guaranteed.

  Those controls, when activated by a timed setting established by various input settings, can establish a continuous delivery mode that is continuous and lasts for a few seconds. For example, a single continuous delivery ultrasound transmission that lasts for a 10 second frequency and intensity duration is determined by the timing circuit. Furthermore, over a specific treatment period, the device can activate the sonicator function at a preset time of the day.

  In certain cases where the patient needs to be involved in his or her illness, the controls can be set to operate by the patient. Treatment of diabetes often requires the patient to self-regulate insulin administration or to give more doses before meals. In such cases, the patient has direct access to the control.

The Applicant has confirmed that most diabetics require up to 36 units of insulin per day. Each unit corresponds to about 40 micrograms of active insulin. A typical type 1 diabetic patient weighing 154 lbs would utilize 1440 micrograms or 1.4 milligrams per day. For patients with type 2 diabetes, delivery needs may vary depending on the body's ability to produce insulin. There are several schedules that can be input into the timing circuit of the device to provide a basic delivery schedule suitable for diabetic patients.

  The device keypad will be programmed to deliver the appropriate ultrasound dose to the skin via the timing circuit to induce the pancreas to release the appropriate amount of insulin on demand. .

  The Applicant recognizes that the amount of glucose in a diabetic patient can vary over time and that large amounts of insulin can be required before a meal. The device of the present invention can be designed to allow diabetics to secure large doses or gains on demand before meals. FIG. 2 is a diagram illustrating a control panel of a device that can be modified to meet delivery therapy and control for a particular drug delivery protocol. Although the control in the illustrated design allows for mass instantaneous delivery, alternative designs for the control functions are possible. Applicants are aware of a glucose monitor that is being introduced to the market that is alleged to be non-invasive and continuous. The system can be applied to the device to provide sensor data so that the unit provides an on-demand amount of drug in response to data from the glucose monitor.

  Applicants may also be able to provide a pressure wave effect across the skin and into the internal structure of the body through the use of alternating waveforms while minimizing the amount of energy transferred to the surface of the skin. I found it. Referring to FIG. 3, the preferred embodiment employs a waveform that changes from a sawtooth waveform to a square wave. The amplitude and intensity of wave formation is theorized to provide a harmonic resonance effect within the target organ. Applicants theorize that the short peak of the ultrasonic waveform in the saw waveform helps to avoid destructive frequencies and cavitation to the skin and underlying tissue. When converted to a square wave, ultrasonic transmission massages tissue or organ structure. In the case of the pancreas, the Applicant theorizes that due to the harmonic effect, the amount of insulin and c-peptide in the organ is released directly into the bloodstream of the vascular network.

  The sonic energy wave generated by the sonic applicator device (1) originates from the transducer assembly (2) on the skin surface and traverses the patient's tissue.

  From there, the ultrasound transmission acts as a carrier wave and enters the target organ from the cortex through the patient's musculature. The carrier is then theorized to induce the organ to release enzymes, endorphins, or other biological compounds within the organ. In the case of diabetes, insulin released in response to ultrasonic transmission moves into the bloodstream as it is.

  The system will utilize ultrasound to improve the pancreas' ability to release insulin through the following modes of operation.

  1. Ultrasonic transmission activates or stimulates the pancreas to release insulin without the use of any associated drugs.

  2. Ultrasound transmission uses an associated drug to activate or stimulate the pancreas to release insulin for the purpose of enhancing the body's ability to use insulin.

  3. Ultrasonic transmission activates or stimulates the drug to increase its effectiveness in insulin therapy or diabetes therapy.

  As noted above, the reason why ultrasonic energy affects drug delivery through the skin is not yet fully understood, but its effect has been fully demonstrated. Applicants may influence drug delivery through other means of guiding the organ to release biological compounds on demand through the use of ultrasound transmission focused on specific periods within the body. Theorized that can be done.

Experiment # 1: illustrated in the graph of Figure 7
A 350 gram test rat was anesthetized and allowed to stand for 30 minutes. Blood samples were taken from rat veins every 10 minutes and the samples were tested with a glucometer device known as a YSI model YSI2300 Stat Plus device to determine glucose levels. FIG. 7 is a graph showing the normal glucose distribution of normal test rats. The Y axis is the amount of glucose measured in units of mg / dl (blood). This test provides a baseline glucose level for normal rats.

Experiment # 2: illustrated in the graph of Figure 8
A 350 gram test rat was anesthetized and allowed to stand for 30 minutes, at which time the animal was exposed to ultrasound for 30 minutes. The ultrasonic level was an intensity of 125 mW / sq.cm and a frequency of 17 kHz.

  Blood samples were taken from rat veins every 10 minutes and the samples were tested with a glucometer device known as a YSI model YSI2300 Stat Plus device to determine glucose levels.

  FIG. 8 is a graph showing the glucose distribution of 350 grams of test rats exposed to ultrasound continuously for 30 minutes. The Y axis is the amount of glucose measured in units of mg / dl (blood). In this experiment, it can clearly be seen that the amount of glucose in a living animal can be reduced using only ultrasound. It is theorized that glucose reduction was achieved by the release of insulin from the test animal pancreas.

Summary To facilitate the release of insulin, the present invention allows several important advantages over the prior art.

  1. The invention described herein addresses the delivery needs of certain patients through the use of ultrasound transmission focused on the pancreas as a means of guiding the pancreas to release insulin on demand by the device. To meet, a portable device is provided that can be tuned to deliver basic and bulk instantaneous delivery of insulin at various time intervals.

  2. Portability is provided by a wearable device rather than just a device assumed in the prior art, which is managed on a schedule that the patient carries and the patient remembers and adheres to.

  3. The present invention provides a system for inducing insulin with or without accompanying chemotherapy or drugs.

  4. The present invention is based on a programmed system at the timing of administering a specific amount of insulin required for drug delivery treatment of a specific patient through ultrasonic stimulation of the patient's pancreas with ultrasound. A means of providing both insulin delivery and massive instantaneous insulin delivery is provided.

  5. Applicants have confirmed that transmission in both sonic and ultrasonic ranges can be illuminated to be effective for the present invention.

  6. The portable programmable sonicator of the present invention provides a suitable drug treatment while allowing the patient to continue daily life, thereby requiring a disease or condition that requires regular administration of the drug This will improve the quality of life of patients with cancer. In addition, perceptually disabled, elderly and quite young people can receive medication under much less supervision.

Presentation of reference Provisional patent application USPTO 60 / 348,306 filed on January 15, 2002 (Bruce K. Redding Jr., PO Box 759, Broomall Pa. 19008).

Information disclosure statement Bibliography and other patent documents are from the first inventor.

Cited Reference US Patent Gazette

Other literature
1.Griffin, JE et al., "Ultrasonic movement of cortisol into pig tissue" Amer. J. Phys. Medicine (1965) 44 (1): 20-25.
2.Griffin, JE et al., "Physiological effects of ultrasonic energy as it is used clinically" J. Amer. Phys. Therapy Assoc. (1966) 46: 18-26.
3.Griffin, JE et al., "Patients treated with ultrasonic driven hydrocortisone and with ultrasound alone" Phys. Therapy (1967) 47 (7): 594-601.
4.Griffin, JE et al., "Low-intensity phonophoresis of cortisol in swine" Phys. Therapy (1968) 48 (12): 1336-1344.
5.Griffin, JE et al., "Effect of ultrasonic frequency on phonophoresis of cortisol into swine tissues" Amer. J. Phys. Medicine (1972) 51 (2): 62-72.
6. Kost, J. et al., "Effect of therapeutic ultrasound on skin permeability" Proceed. Intern. Symp. Control. Rel. Bioact. Mater. (1989) 16 (141): 294295.
7.Lutz, H. et al., Manual of Ultrasound: Basic Physical and Technical Principles (1984) (Berlin: Springer-Verlag) Chapter 1.
8.Miyasaki, S. et al., "External control of drug release: controlled release of insulin from a hydrophilic polymer by ultrasound irradiation in diabetic rats" J. Phann. Pharmacol. (1988) 40: 716-717.
9. Skauen, DM et al., "Phonophoresis" hit. J. Pharmaceutics (1984) 20: 235245.
10.Tyle, P. et al., "Drug delivery by phonophoresis" Pharmaceutical Research (1989) 6 (5): 355-361.
11.Eppstein, DA et al., "Applications of Liposome Formulations for Antimicrobial / Antiviral Therapy" Liposomes as Drug Carriers 311, 315 (G. Gregoriadis ed. 1988).
12.Eppstein, DA, "Medical Utility of Interferons: Approaches to Increasing Therapeutic Efficacy" 7 Pharmacy International 195-198 (1986).
13.Eppstein, DA et al., "Alternative Delivery Systems for Peptides and Proteins as Drugs" 5 CRC Reviews in Therapeutic Drug Camer Systems 99, 125 (1988).
14.Ulashik, VS et al., Ultrasound Therapy (Minsk, Belarus 1983).
15.Apfel, RE, Possibility of Microcavitation from Diagnostic Ultrasound, IEEE Trans.Ultrason. Ferroelectronics Freq.Control UFFC-33: 139-142 (1986).
16. Barry, "Mode of Action of Penetration Enhancees in Human Skin," J. Controlled Rel. 6: 85-97 (1987).
17. Gaetner, W., "Frequency Dependence of Ultrasonic Cavitation," J. Acoust. Soc. Am. 26: 977-980 (1954).
18.Kost and Langer, "Ultrasound-Mediated Transdermal Drug Delivery," Topical Drug Bioavailability Bioequivalence and Penetration (Maibach, HI, Shah, VP, Editors, Plenum Press, New York) 91-104 (1993).
19.Kost, et al., "Ultrasound Effect on Transdermal Drug Delivery," (Ben Gurion University Dept. of Chem. Engineering, Beer Sheva Israel) (MIT, Dept. of Applied Biological Sciences, Cambridge, MA) CRS Aug. 1986 .
20.Krall, LP, World Book of Diabetes in Practice (Editors, Elsvier, 1988).
21.Levy, et al., "Effect of Ultrasound on Transdermal Drug Delivery to Rats and Guinea Pigs," J. Clin. Invest. K 83: 2074-2078 (1989).
22.Liu, et al., "Co-transport of Estradiol and Ethanol Through Human Skin InVitro: Understanding the Permeant / Enhancer Flux Relationship," Pharmaceutical Research 8: 938-944 (1991).
23. Machluf and Kost, "Ultrasonically enhanced Transdermal Drug Delivery. Experimental approaches to elucidate the mechanism," J. Biomater. Sci. Polymer Edn. 5: 147-156 (1993).
24.Mitragotri, et al., "Ultrasound-Mediated Transdermal Protein Delivery," Science 269: 850-853 (1995).
25.Mitragotri, et al., "A Mechanism Study of Ultrasonic-Enhanced Transdermal Drug Delivery," J. Pharm. Sci. 84: 697-706 (1995).
26.Mitragotri, et al., In. Encl. Of Pharm Tech .: Swarbrick and Bovian, Ed., Marcel Dekker (1995) *.
27.Monmoto, Y., et al., "Prediction of Skin Permeability of Drugs: Comparison of Human and Hairless Rat Skin," J. Pharm. Pharmacol. 44: 634-639 (1991).
28. Newman, J., et al., "Hydrocortisone Phonophoresis," J. Am. Ped. Assoc. 82: 432-435 (1992).
29.Perry, et al., "Perry's Chemical Engineering Handbook" (McGraw-Hill, NY 1984).
30.Potts and Guy, "Predicting Skin Permeability," Pharm. Res. 9: 663-669 (1992).
31.Prausnitz, et al., "Electroporation of mammalian skin: A mechanism to enhance Transdermal Drug Delivery," Proc. Nat]. Acad. Sci. USA 90: 10504-10508 (1993).
32.Quillen, WS, "Phonophoresis: A Review of the Literature and Technique," Athl. Train. 15: 109-110 (1980).
33. Tyle and Agrawala, "Drug Delivery by Phonophoresis," Pharm. Res. 6: 355-361 (1989).
34.DM Skauen and GM Zentner, "Phonophoresis", Int. J. Pharm. 20, 235245, (1984).
35.Yagihashi et al Effect of Aminoguanidine on Functional and Structural Abnormalities in Peripheral Nerve of STZ-Induced Diabetic Rats, Diabetes, vol. 41, Jan. 1992, pp. 47-52.
36.Liedtke et al, Transdermal Insulin Application in Type 11 Diabetic Patients I Results of a Clinical Pilot Study Drug Research, 40 (11) NI 8, 1990, pp. 884-886.
37.Stephen et al, Potential Novel Methods for Insulin administration, Biomed. Biochem. 5, 1984, pp. 553-558.
38.Mitragotri, Samir et al. "A Mechanistic Study of Ultrasonically-Enhanced Transdermal Drug Delivery," (1995) Journal of Pharmaceutical Sciences, vol. 84, No. 6, pp. 697-706.
39.Memon, Gopinathan K. et al. "High-Frequency Sonophoresis: Permeation Pathways and Structural Basis for Enhanced Permeability," (1994) Skin Pharmacol, 7: 130-139.
40.Bommannan, D. et al. "Sonophoresis 11. Examination of the Mechanism (s) of Ultrasound-Enhanced Transdermal Drug Delivery," (1992) Pharmaceutical Research, vol. 9, No. 8, pp. 1043-1047.
41.Bommannan, D. et al. "Sonophoresis. I. The Use of High-Frequency Ultrasound to Enhance Transdermal Drug Delivery," (1992) Pharmaceutical Research, vol. 9, No. 4, pp. 559-564.
42.Elias, Joel J. "The Microscopic Structure of the Epidermis and Its Derivatives," (1989) Percutaneous Absorption, Marcel Dekker, Inc. New York and Basel, pp. 1-12.
43.Pratzel, Helmut et al. "Spontaneous and Forced Cutaneous Absorption of lndomethacin in Pigs and Humans," (1986) The Journal Of Rheumatology, vol. 13, No. 6, pp. 1122-1125.
44.Burnette, Ronald R. "lontophoresis," Chapter 11, pp. 247-291.

Although the present invention has been described in detail above, there are several variations on device design and functionality, and those skilled in the art will appreciate that such design and functionality variations are included within the scope of this disclosure. You will understand.

1 is a depiction of the present invention placed on a patient's abdomen. FIG. FIG. 2 is a diagram of a control device for inducing an ultrasound signal in a patient's skin for the treatment of diabetes. It is a figure which shows utilization of the conversion from the alternating waveform produced | generated by the frequency driver of this invention, ie, a sawtooth waveform to a square wave. FIG. 6 illustrates a transducer device design suitable for use with the present invention utilizing a cymbal design. 2 is a photograph of a cymbal transducer element. FIG. 6 shows a design for use of a plurality of transducers arranged in an array configuration. FIG. 2 is a graph showing normal glucose distribution for 350 gram test rats. FIG. FIG. 2 is a graph showing normal glucose distribution for 350 gram test rats. FIG.

Claims (17)

  A method for inducing the release of an active biopharmaceutical composition from various organs, glands, or other anatomy in an individual's body, through a transducer device worn on the patient's body and worn by the patient throughout the day Applying the ultrasound, wherein the transducer device is controlled by a portable programmable ultrasound regulator device that is itself worn by the individual to regulate the ultrasound to the individual of the active biopharmaceutical composition And a method of applying over a strength and time effective to allow transfer of a therapeutic amount of the active biopharmaceutical composition from the target organ, gland or other anatomy for the purpose of timed drug delivery.   The method of claim 1, wherein the ultrasound has a frequency in the range of about 20 kH to 10 MHz.   2. The method of claim 1, wherein the intensity of the ultrasound is in the range of about 0.01 W / cm.sup.2 to 5.0 W / cm.sup.2.   The method of claim 1, wherein the wearable portable sonic device is attached or connected to a transducer device that provides delivery of ultrasound to a specific organ, gland or other anatomy of an individual.   As a means of simultaneously injecting sonic energy while minimizing the effects of sonic cavitation on the skin, or internal body structures or organs, the ultrasonic signal is, for example, in a waveform pattern alternating from a sine wave to a square wave or from a sawtooth waveform to a square wave 2. The method of claim 1, wherein the method is configured.   2. The method according to claim 1, wherein ultrasonic waves are continuously applied.   The method of claim 1, wherein the ultrasound is pulsed.   The apparatus of claim 1, wherein the transducer assembly comprises a single cymbal ultrasonic transducer.   2. The apparatus of claim 1, wherein cymbal ultrasonic transducers are employed in the transducer assembly array.   2. The means for transmitting ultrasound to a target organ within a patient's body according to claim 1, wherein the plurality of transducer elements transmit ultrasound of the same frequency and intensity as each other.   2. The means for transmitting ultrasound to a target organ within a patient's body according to claim 1, wherein the plurality of transducer elements transmit ultrasound of different frequencies and intensities.   2. The assembly of claim 1, wherein the transducer is a fifth-type flexural transducer “cymbal” type electrically connected to the ultrasonic waveform generator.   2. The assembly of claim 1, wherein the transducer is an array of several fifth-type flexural transducer cymbal elements electrically connected to the ultrasonic waveform generator.   The assembly according to claim 1, comprising at least one basic time series and at least one mass instantaneous time series microprocessor means for guiding an organ to release said biopharmaceutical composition.   A method for inducing release of insulin from within an individual's pancreas, comprising applying ultrasound through a transducer device worn on the patient's body and worn by the patient throughout the day, the transducer device itself Controlled by a portable programmable ultrasound regulator device worn by the individual, wherein the ultrasound is used to provide a controlled and timed drug delivery of the insulin to the individual with a therapeutic amount of insulin from the pancreas. A method applied over an intensity and time effective to allow movement.   16. The method of claim 15, wherein ultrasound transmission is utilized to affect insulin release from the pancreas to treat type 1 and type 2 diabetes.   A method for inducing the release of an active biopharmaceutical composition from various structures within an individual's body, comprising applying ultrasound through a transducer device that is implanted within the patient's body and worn by the patient throughout the day. The transducer device is controlled by a portable programmable ultrasonic regulator device that is implanted by the individual or worn external to the individual's body, the ultrasonic waves of the active biopharmaceutical composition A method applied over an intensity and time effective to allow transfer of a therapeutic amount of the active biopharmaceutical composition from a target organ for the purpose of coordinated and timed drug delivery to an individual.

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