NON-INVASIVE TRANSDERMAL ULTRASOUND WATCH



NON-INVASIVE TRANSDERMAL ULTRASOUND WATCH

Background:

The invention is generally in the area of drug delivery, and particularly improved method for transdermal drug delivery using ultrasound atomizing transducers at low frequencies. Reference: Pub. No.: WO/1997/004832

Transdermal drug delivery (TDD) offers several advantages over traditional delivery methods including injections and oral delivery. When compared to oral delivery, TDD avoids gastrointestinal drug metabolism, reduces first- pass effects, and provides sustained release of drugs for up to seven days, Reference: Elias, In Percutaneous Absorption: Mechanisms- Methodology -Drag Delivery. , Bronaugh, R. L.

The word "transdermal" is used herein as a generic term. However, in actuality, transport of drugs occurs only across the epidermis where the drug is absorbed in the blood capillaries. When compared to injections, TDD eliminates the associated pain and the possibility of infection. Theoretically, the transdermal route of drug administration could be advantageous in the delivery of many therapeutic proteins, because proteins are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake, proteins such as interferons are cleared rapidly from the blood and need to be delivered at a sustained rate in order to maintain their blood concentration at a high value, and transdermal devices are easier to use than injections. Ultrasound has been shown to enhance transdermal transport of low-molecular weight drugs (molecular weight less than 500) across human skin, a phenomenon referred to as sonophoresis (Levy, J". Clin Invest . 1989, 83, 2974-2078; Langer, R. , In "Topical Drug Bioavailabili ty, Bioeguivalence , and Penetration " ; pp. 91-103, Shah V. P., M.H.I. , Eds. (Plenum: New York, 1993) ; Frideman, R. M. ,' Interf erons : A Primer' , Academic Press, New York, 1981) ) .

U.S. Patent Nos. 4,309,989 to Fahim and 4,767,402 to Kost, et al., disclose various ways in which ultrasound has been used to achieve transdermal drug delivery. Sonophoresis has been shown to enhance transdermal transport of various drugs. Although a variety of ultrasound conditions have been used for sonophoresis, the most commonly used conditions correspond to the therapeutic ultrasound (frequency in the range of 1 MHz - 3 MHz, and intensity in the range of 0 - 2 W/cm2) (Kost, Jn Topical Drug Bioavailabili ty Bioequivalence and Penetration, pp. 91-103, Maibach, H. I., Shah, V. P. (Ed) Plenum Press, New York, 1993; U.S. Patent No. 4,767,402 to Kost, et al.).

Previous suggestions for a device for transdermal drug delivery suggested comprising a drug reservoir and an ultrasonic membrane transducer adapted to cooperate with drug reservoir, ultrasonic membrane transducer comprising at least two transducer elements forming a transducer array, each transducer element having a membrane, a number of electrodes disposed on a surface of each transducer element and coupled to the membrane for applying an electrical field to flex the membrane in order to generate an ultrasonic signal, and a control unit for separately controlling the application of the electrical field to flex the membrane of each transducer element in such a way that the ultrasonic signals emitted by the transducer elements exhibit phase differences resulting in a focusable overall ultrasonic signal of the transducer array, Reference: (WO2007144801): (device for transdermal drug delivery and method of operating such a device)

This device can be used for non-invasive drug delivery for patients; for example, diabetic Patients hope to find a way to deliver insulin into the blood other than needle injection, which is painful and sometimes causes infections because of using needles more than once. Transdermal drug delivery through ultrasound has been tested before, animal experiments were made on rats, pigs and rabbits; the proof of transferring insulin by ultrasound to skin was achieved, while using different frequencies, intensities, surface area and exposure time, trying to seek the best circumstances for drug delivery.

Technical field:

The subject device is basically made out of two parts:

The first part includes the ultrasound transducer with a reservoir and a housing thermoplastic piece this part is to be placed on the inner arm of the elbow, with a silicon material surrounding the transducer to prevent leakage of the drug; the ultrasound transducer is connected with the second part through two small wires covered by a silicon for insulation.

The second part contains a printed circuit board with its components which will drive the transducer at its optimal frequency, as well as driving the LCD screen with the buttons to let user specify time needed to complete the delivery of drug such as insulin. This time will depend on the dose in a predefined database for the patient; it will differ from one person to another due to the variety of skin permeability. Power needed to drive this circuit is relatively small; for example a specific voltage will be supplied from a rechargeable batteries, the whole system will be fitted on the arm like a watch, easy to use and light for the patient to carry with.

Technical Background

The invention depends on previous animal experiments to prove ultrasound insulin delivery through skin by increasing the permeability by the cavitation theory; the current theory states that cavitation events open reversible channels in the lipids layers of the stratum corneum and provide less tortuous paths of transport for proteins such as insulin. Electron microscopy on skin exposed to low frequency ultrasound revealed the removal of surface cells and the formation of large pores and pockets (~20 μm), large enough to accommodate transport of proteins and other large molecules. By increasing the pores in the outer skin layer through ultrasound with a low frequency; drug delivery of proteins will transfer from the stratum corneum to the skin layers achieving the capillary beds which lie on the inner skin layers. A device with at least one ultrasound transducer which has a very small micro nozzles (7-10 μm) which is used to let the drug which will be at the beginning on the upper side of the transducer, to be transferred to the lower side of the transducer which will be in a direct contact with the patient's skin.

Exposition of an invention:

To prove the feasibility of this device; it has been applied on animals (wistar rats) at Jordan University of Science and Technology-Animal house to specify the amounts of drug needed and time required to transfer doses of, say, insulin through skin. First specific amounts of say: insulin will be placed on a specific reservoir, which is in direct contact with the upper part of the ultrasound transducer which in turn, its lower part is in direct contact with the skin. To turn on the device; user have to specify time needed for that dose of the drug to be transferred according to some previous trails and experiments on that device, user will have a manual to illustrate the required dose with the optimal time needed for that dose to be fully beneath skin, for example time needed for a 6 units of insulin to be transferred from the ultrasound transducer penetrating the skin is 20 minutes, then every extra 3 units after the first 20 minutes will then need only 5 minutes because at the first 15 minutes the transducer will be working on increasing skin permeability, after that, pores on the skin will be larger and drug will easily be transferred reaching the capillary beds on the inner skin layers.

Descriptions of diagrams and sketches:

Details of manufacturing the prototype of the device:

Figure 1 shows the type of ultrasound transducer which is an Ultrasonic Vibration Micro Nozzle type with a rectangular shape with a resonant frequency of 135 KHz ± 5 KHz. The housing procedure for this ultrasound transducer includes the following circumstances:

• To insure that the driving electrode (white color part of the transducer) and the PZT part (silver color part of the transducer) is completely well insulated from the skin and insulin being introduced to it, the design will separate the two parts of the transducer; the white piece will gather the wires and fully insulate them, and the silver piece will contain the insulin reservoir with the US plate being in a direct contact with the skin.

• Insulin for example has to be kept at a certain region “reservoir”, thus; it is important to have this reservoir made of non-contaminated materials, also the dose of say insulin that will be delivered to the patient was calculated according to some lab experiments and was compared with the doses required in the normal insulin syringes (needle injection).

• The driving circuit of the transducers depends on the resonant frequency, i.e.: the driving circuit of the transducer which has a 135 KHz is shown in figure 2.

• Using a 3-D prototyping machine, the housing procedure has been made for the transducer, keeping in mind to have the insulin reservoir made of non-contaminated material (i.e.: Glass or plastic) when introducing insulin inside it.

• The nozzle size of the 135 KHz transducer is 7-10 micrometers, while the insulin particles diameter is about 4 nanometers, indicates that the insulin will pass through the nozzles of the US transducers toward the skin, skin permeability is an important issue in this field; since the insulin will eventually pass through the skin, it is important to choose the more permeable and comfortable region to apply the device on, according to dermatologist consultation; the more reliable and permeable region is found to be at the inner part of elbow.

• In order to have non-contaminated insulin entering the body through the skin, some circumstances have to be taken into consideration, considering the entire pathway that insulin will cross (from the reservoir to the ultrasound transducer and at last to skin “see figure 3”).

• The reservoir of insulin has to be glass or silicon made, the insulin will be in a direct contact with the Ultrasound (US) transducer, so the material of the transducer should be non toxic and do not react with insulin. Form the data sheet; micro nozzles are made from Gold plated nickel alloy which is found to be safe for insulin.

From the above factors; the housing of the ultrasound transducer has been made to suite the inner arm of the elbow and with considering safety factors.

Figure 4 shows ultrasound transducer before housing, this transducer has dimensions of 29.1 mm length and 17.3 mm width and 1 mm thickness, with small micro nozzles (7-10 microns) the white part is the PZT element and the silver part which have a smaller thickness of about 50 micro meters, this part will be connected to a reservoir from the upper side and to be in a direct contact with the skin from the lower side. The PZT element with the two wires will be isolated from the skin using an adhesive medical silicon material.

Figure 5 shows the housing procedure, with a thermoplastic material being made using a 3-D printer with dimensions suites the transducer and with a curvature to fit the inner side of the elbow on the user hand, above the transducer; a reservoir has been made with the transducer to be the base of this reservoir and a silicon or rubber cap for covering the upper part of it, to be suitable for the drug delivery system which will varies according to user from the simplest insertion of drug through needle inside the reservoir to a micro pumping mechanism integrated by the circuit and attached to that reservoir.

Figure 6 shows Ultrasound transducer being housed; top view on the left side with a reservoir for drug being in direct contact with this part of transducer and bottom view on the right side being in a direct contact with human skin, medical silicon material was applied on this part as well as a Velcro tape to insure there is no drug leakage outside the exposure area.

Figure 7 illustrates how this device is made to fit the inner side of elbow in the human arm, figure 18 and 19 shows the complete device as a prototype, and its size related to a ruler.

Means of invention implementation:

Details about results of animal experiment applied to test the device:

In order to test the device on a membrane to insure the transfer of drug using ultrasound; an animal experiment was made to test insulin delivery through ultrasound with the following specifications:

1. Wistar rats to be used and treated as a diabetic case study. In order to have the rat in an abnormal blood glucose level case, a mixture of ketamine-xylazine anesthetic agent was used; the xylazine cause a hyperglycemia in blood.

2. The anesthetic agent (Ketamine-Xylazine mixture) was administered intramuscularly after anesthetizing the rat temporary with ether gas to control the anesthetizing procedure.

3. The Control group which was made to specify the base line of the insulin level as well as the blood glucose level in the rats, this group of rats included some rats being anesthetized. Both blood glucose level and insulin levels in blood was monitored by taking blood samples to the laboratory to analyze for the insulin test (two for each rat; one blood sample immediately after anesthesia and the other blood sample after 70 minutes of time), and by take blood glucose level every 10 or 20 minutes via a glucometer for 70 minutes.

4. Insulin delivery with no Ultrasound was also tested on a group of rats, a normal needle injection for insulin was made (invasive delivery), this test was made under aesthesia, using an insulin syringes with a dose of (0.1) units on the rat’s abdomen.

5. Using the ultrasound device and applying it to a number of rats, the abdominal area of the rats was shaved and cleaned from any remaining hair to become the area of exposure to ultrasound waves. At the zero time; before applying the device with insulin, blood glucose level was tested by withdrawing blood sample from the tail as well as a blood sample was taken by a heart puncture to test initial insulin levels in the blood, after that, the ultrasound device was prepared and time needed for the experiment as well as doses was determined, the device was turned on by following the LCD instructions while putting the ultrasound at a proper place on the abdomen, The abdomen area of the rat and the transducer is then in a direct contact. By holding the transducer in a well fixed area without touching the vibrating part of it; drops of insulin was applied using an insulin pen (with a predefined dose of insulin according to user), note that this transducer is not being affected by the air bubbles, the insulin will be putt drop by drop until being absorbed and transferred to the capillary beds, measurements of blood glucose level each 10 minutes after turning on the ultrasound transducer was made as well as after 70 minutes of time, another blood sample was taken by heart puncture of the rat and to be analyzed in the laboratory to measure insulin being transferred via the ultrasound device.

Figure 8 shows blood glucose measurements made by glucometer over 80 minutes; the first rat was tested before applying the anesthetic agent to insure the effect of that anesthesia in raising blood glucose levels abnormally to have the rats as a fake diabetes cases, blood samples was withdrawn from the animal's tail every 20 seconds. The readings shows a general increasing in blood glucose level and the average blood glucose levels is shown in figure 9.

Figure 10 shows insulin levels in blood at time zero; that is immediately after anesthesia, and after 80 minutes from anesthesia, since blood samples have to be analyzed in a proper way for measuring the insulin levels; blood samples of size 2 ml was withdrawn from the heart directly by a heart puncture made by a specialist veterinarian, those samples was saved in a heparin tubes and taken to a known laboratory at Amman to test the insulin levels. As noticed from the chart in figure 11, insulin levels are nearly constant, because the rats are under anesthesia and the pancreas has a low activity according to anesthesia, which is in usual cases inserts insulin in the blood stream.

Figure 12 shows the readings of blood glucose levels in rats after applying ultrasound insulin delivery device on the abdomen area of each rat. These readings shows a significant decrease in blood glucose levels with time, an indication of the presence of insulin in blood, because insulin receptors which lies on the body cells who needs glucose, these receptors will bind with insulin from blood at the surface site of the body cells, letting the glucose gates open and the transfer of glucose from the blood to inside the cells occurred, so that a significant decrease in glucose levels in the blood occurred. The first two rats in the table had a 3 units of insulin, and the third rat had 6 units of insulin, a very good result in the last rat appeared because as this method of injecting insulin inside the skin gradually is non-invasive, it is expected to have some wasted or stuck insulin inside the skin layers until the amount of insulin is high enough to push insulin to the layer which contains the capillary beds which in turn will intake insulin to the blood circulation. This amount of wasted or stuck insulin was found to be 3 units at maximum cases. Figure 13 is a chart shows every rat's blood glucose level and the average blood glucose levels on those rats, despite of the differences of the doses being administered in the first two rats and the last rat. Figure 14 illustrates insulin levels being analyzed at the lab at time zero and after 80 minutes, a very obvious increase in specs of insulin in blood can be seen from figure 15 after applying ultrasound with insulin delivery, rat number two here was given a 6 units of insulin, and it is obvious that insulin level in this rat increased much higher than other rats which was given only a 3 unites of insulin. The laboratory which analyzed the results gave this second rat a net difference of 2.3 units of insulin before and after 80 minutes, this dose indicates that 3 units of insulin was wasted or stuck in the skin layers, keeping in mind that stuck insulin will not have any side effects in the skin, it will be eliminated by the body after that. Calculating the injected dose of insulin which was 6 unites and subtracting 3 unites as a stuck insulin, keeps 3 units of insulin in the blood; and because the insulin receptors will bind with insulin in the blood, a small amount of insulin will be consumed in opening the glucose gates, say 0.7 units of insulin, keeping a 2.3 unites in blood which was measured in the lab, which indicates the accuracy of the procedure and the success of the device to transfer insulin to the blood.

Figure 16 compares the average blood glucose levels in the two groups; the control group and the ultrasound insulin delivery group, the difference of the two initial levels of blood glucose and the two final levels of blood glucose indicates the effectiveness of the ultrasound insulin delivery device being able to transfer amounts of insulin able to decrease the glucose levels in blood.

Figure 17 show a comparison between average insulin levels in blood in both control and ultrasound insulin delivery groups. A significant increase of insulin levels appears at the ultrasound insulin delivery group.

Note that the initial levels of all data in the chart are not the same because of the fact that initial blood glucose level and insulin level in blood differs from one rat to another, according to their weights, keeping in mind that the rats were not fasted before the experiment, so that the levels are different also because of what the rats ate before the experiments.

Manufacturing details:

Design of the transducer house which will include the reservoir as well is preferred to be of 3 sized, to cover all the possible sizes for human's arms. Ultrasound transducer used will be with the same frequency for all users, as well as the driving circuit and the size of the printed circuit board which will gather all the components upon it. Users will have a guidance manual which will contain the permeability test that every user has to make before using the device, to know how permeable his skin is and to define the initial time needed to operate the transducer in order to increase the size of pores in the skin. This device will vary from one used to another in the operating time only, and the frequency will be constant for all users. Another circumstance has to be taken into consideration is that the doses required for the device will be slightly greater than the normal doses taken by needle injection (invasively); since the device offers a non-invasive method for delivering drugs gradually from the upper part of the skin, reaching the inner part of the skin which includes the capillary beds, so more dose needed in order to let the drug particles push each other to reach that area inside the skin. This dose will be determined according to how much fats appears on the user's arm, specifically in the inner elbow side, this dose will be no more than 0.03 ml.

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