Title of Invention	TRANSCUTANEOUS THERMOELECTROPORIC OMNIMOLICULAR DRUG DELIVERY SYSTEM
Abstract	The present invention provides a system and a method of drug delivery that uses specialised thermal energy combined with high energy electroporation to first alter the skin barrier (stratum corneum, the topmost layer of the skin that serves as the greatest barrier to drug diffusion), and next to increase the energy of drug molecules. This way one can even transfuse macromolecules like insulin transcutaneously without the use of needles.

Title of Invention

TRANSCUTANEOUS THERMOELECTROPORIC OMNIMOLICULAR DRUG DELIVERY SYSTEM

Abstract

The present invention provides a system and a method of drug delivery that uses specialised thermal energy combined with high energy electroporation to first alter the skin barrier (stratum corneum, the topmost layer of the skin that serves as the greatest barrier to drug diffusion), and next to increase the energy of drug molecules. This way one can even transfuse macromolecules like insulin transcutaneously without the use of needles.

Full Text	This invention relates to transcutaneous thermoelectroporic omnimolicular drug delivery system, hereinafter referred to as "T2OD2", which is used for the application of a drug to the skin to achieve systemically active levels of the drug to treat diseases remote from the application site and a method of drug delivery. Transcutaneous delivery is an important delivery route that delivers precise amounts of drug through the skin for systemic action. Various types of drug delivery systems, such as Bioadhesive, Hyaluronic, Proliposomal, Osmotic drug delivery systems, are known in the art. One of the oldest forms, that has existed for of several centuries, for applying medicaments locally through patient's skin, and for applying medicines to the eyes and ears is Iontophoresis. It is also known to apply an electric field to the skin to greatly enhance the skin's permeability to various ionic agents. The use of Iontophoresis has helped to obviate the need for hypodermic injection and also it avoids the problems of trauma, pain and risk of infection to the patient. A rich area of research over the past 10 to 15 years has been focused on developing transdermal technologies that utilize mechanical energy to increase the drug flux across the skin by either altering the skin barrier (primarily the stratum corneum) or increasing the energy of the drug molecules. These so-called "active" transdermal technologies include iontophoresis (which uses low voltage electrical current to drive charged drugs through the skin), electroporation (which uses short electrical pulses to create transient aqueous pores in the skin), sonophoresis (which uses low frequency ultrasonic energy to disrupt the stratum corneum). Even magnetic energy, coined magnetophoresis, has been investigated as a means to increase drug flux across the skin. Of these technologies, only iontophoresis has been successfully developed into a marketable product, albeit for local pain relief. Most of the currently available form of transdermal drug delivery system uses a technique called drug-in-adhesive, which is used in patches like the nicotine patch. "T2OD2", of the present invention, is a non-invasive means for providing continuous transcutaneous drug infusion to a patient, similar to intravenous administration, except that the drug is delivered from specially designed delivery port applied to the skin, which eliminates the need for vascular access and syringes or pumps. The major advantages provided by this kind of drug delivery technique include the following: Improved bioavailability: avoidance of the first-pass metabolism by the liver as in the case of oral dosage forms. More uniform plasma levels: controlled zero-order absorption through the stratum corneum into the systemic circulation so as to reduce periods of underdosing and oversdosing. Longer duration of action: ability of the "T2ODr to adhere to the skin for as long as 7 days, resulting in a reduction in dosing frequency. Reduced side effects: due to reduction of the peaks in plasma levels unlike what results from conventional oral dosage forms. Improved therapy: due to maintenance of plasma levels up to the end of the dosing interval compared to a decline in plasma levels with conventional oral dosage forms. Improved patient compliance: due to the reduced dosing frequency and reduction of system side effects. Noninvasive dosing: elimination of local infection associated with subcutaneous, intramuscular or intravenous injections. Reversible action: removal of the "T2OD2 " port can reverse and adverse effects due to overdosing. Easily Available Drug forms: Drugs filled in soft capsule, similar to oral dosage forms can be adopted with minor changes for use in this invention. Today pharmaceutical companies face two major problems. The patent protection for many established drugs are coming to an end and new biotechnology-derived products, namely peptides and proteins or even nucleic acids, are either metabolised when administered intravenously or broken down by the digestive system when delivered orally. Drug delivery is the field of research, which promises to solve these challenges. The primary object of the present invention is to address the above issues. The present invention relates to a Drug Delivery System, which will be called "Transcutaneous Thermoelectroporic Omnimolicular Drug Delivery System (T OD )". The present invention provides a system and a method of drug delivery that uses specialised thermal energy combined with high energy electroporation to first alter the skin barrier (stratum corneum, the topmost layer of the skin that serves as the greatest barrier to drug diffusion), and next to increase the energy of drug molecules. This way one can even transfuse macromolecules like insulin transcutaneously without the use of needles. The A broad spectrum of potential applications of this invention can includes the following: Immunology - where one envisions a single-shot vaccine delivery system capable of pulsatile dosing to immunise against multiple diseases Oncology - where a protein such as an angiogenesis inhibitor is delivered locally at the tumor site Gene therapy - where nucleic acid has to enter the cell nucleus Tissue engineering - where growth factors are released from polymers at appropriate times to promote tissue regeneration In Diabetic patients, who are insulin dependent, this invention will help them to live an almost normal life without injection's everyday. In cancer patients, who are already in pain, painkillers can be effectively given with least side effects and without pricking. This invention will now be described with reference to the accompanying drawings, wherein: Fig. 1 illustrates the drug delivery system comprising the Control unit and Delivery port; and Fig. 2 illustrates the block diagram of the Control Unit. The drug delivery system of the present invention consists of two parts, a control unit with the 0 0 0 0 necessary electronics and the delivery system called T OD -Port. The T OD -Port is a small device as shown in Fig. 1. This device is the interface between the control unit and the body. _^ *^ .^_> O — _-0 — O The T OD is strapped on the surface of the skin using a Velcro strap. The T OD - Port is completely coated with Gold of about 50-micron thickness, to avoid any reaction between the port and the skin and the port and the drug inside port reservoir. The Control unit consists of the following major sub-systems: 1. User Interface and Keyboard 2. System Control Microcomputer 3. Pulse Modulation System 4. Power Supply Controller 5. Electropore Generator 6. Temperature Control System 7. Alarm and Safety Control. User Interface and Key Board: User Interface and keyboard sub assembly consists of a numerical keyboard, to enable the user to input set-up information and a numeric display. Information like the molecular weight, delivery rate etc., are fed into the system from here. System Control Microcomputer (SCM): This is the heart of the system, it contains all the algorithm to perform the complete function of the device. The SCM controls all the other sub-assemblies, it takes in the feed back information from the T OD port and processes the required pulse rates and temperature gradient. Pulse Modulation System: The Pulse Modulation System or PMS accepts commands from the SCM and accordingly modulates the output pulses that are sent to T2 OD2 -Port's gold electrode, which depends on the various set parameters. Power Supply Controller: The power supply controller controls and converts, 4.5v D.C from two batteries to the required power for all the subassemblies. Including the high voltage requirements of the device. It also controls and regulates the current, based on the requirements of the SCM. Electropore Generator: The Electropore Generator is controlled by the SCM, it basically provides for the required e-pore pulsation based on the set programme and voltage and current set by the power supply controller. Electropore Generator is a high precision special pulse generator that actually creates microscopic pores into the different layers of the skin depending on the pre-set parameters. Temperature Control System: Accurate temperature that varies in milli-degrees centigrade is an important aspect of this device. The temperature variations are from room temperature to about 40 degrees centigrade, with accuracy of 0.001 degrees. Precision temperature is what sets the required permeability of the skin, at the time of drug transfusion. Alarm and Safety Control: Any such device that is used for critical application as delivering a life-saving drug should have utmost safety in its operation. Any thing in the operation of the system can go wrong, like the thermoregulatory system, or the electroporation system, which effects the performance of the device. It may even not transfuse the drug or it may change the dosage, while the user has no knowledge about it. This subassembly continuously monitors all the controls and other subassembly and itself for malfunction and any abnormality that is encountered, the device is forced to shut down, even by bypassing the SCM. The subassembly provides alarms in the form of sound and blinking lights on the display of the device and indicating the exact nature of the problem encountered. The delivery port comprises of a flat base 1 made of brass and is completely coated with gold of about 50-micorn thickness, to avoid any reaction between the port and the skin and the port and the drug inside the port. The said base 1 houses a drug compartment 2 with a cap 3 wherein the drug filled in the form of a capsule 4,or the like is placed. The base 1 also houses drug reservoir 5, having a permeable membrane 6, with a diffusion needle 7. The diffusion needle 7 projects into the drug compartment 2. The base 1 also has holders 8 for holding the gold electrodes 9 which are connected to the control unit 10 through the electropore circuit 11. A thermistor 12 is provided for measuring the temperature of the skin surface and feed it back to the controller to maintain the prescribed temperature. And a heat pulser 13 is provided for maintaining a pre-set temperature on the surface of the skin in a pulsed manner, which depends on the characteristics of the drug being delivered. Usage; The usage of the invention starts with the T2OD2 -Port fixed on the skin, various parameters are set using the control unit, like the molecular weight of the drug, rate of release of the drug and setting of any alarm conditions. Now the drug, which will be in a liquid form, filled in a soft capsule. The drug compartment cap 3 is opened and the capsule is deployed, and the lid 3 is closed. The closing of the lid will push the capsule, to be punctured by the diffusion needle 7. The environment in the drug reservoir 5, will start diffusing the drug towards the permeable membrane 6, by this time the stratum corneum, the top most layer of the skin is made porous using molar dependant electroporation increasing the permeability of the skin, and the infrared energy of the thermal pulsation would have accelerated the molecules of the drug. The drug now begins to transfuse through the different layers of the skin, until it reaches the blood stream that carries the drug further in the system. The pores created in the stratum corneum will be closed within 30 seconds after the device is switched off. The device is equipped with feedback systems, measuring the temperature, pulsation rate, voltages and currents and continuously makes alterations to suit environmental changes that may occur around the user. I claim: 1. A transcutaneous, thermoelectroporic, omnimolicular drug delivery system comprising of a control unit and a delivery port, the control unit comprises of an input device, a system control microcomputer, a pulse modulation system, means to control power supply, electropore generator, a thermostat and an alarm, the delivery port comprises of a drug compartment with a lid, a drug reservoir having means for diffusing the drug to be delivered, said means being placed in such a way to establish a connection between the drug compartment and drug reservoir, electrodes for receiving the pulses generated by the electropore generator in the control unit, means for holding the said electrodes, a heat pulser and a thermistor. 2. The drug delivery system as claimed in claim 1, the means for diffusing the drug to be delivered is a diffusion needle placed in the drug reservoir and projecting into the drug compartment. 3. The drug delivery system as claimed in claim 2, wherein the input device is an user interface and keyboard. 4. A method of drug delivery that uses infrared or thermal energy in combination with active electroporation to transport or transfuse all kinds of drugs and chemical substances into the human body through the skin route. DATED THIS 17TH DAY OF SEPTEMBER 2005.

Full Text

This invention relates to transcutaneous thermoelectroporic omnimolicular drug delivery system, hereinafter referred to as "T2OD2", which is used for the application of a drug to the skin to achieve systemically active levels of the drug to treat diseases remote from the application site and a method of drug delivery. Transcutaneous delivery is an important delivery route that delivers precise amounts of drug through the skin for systemic action.
Various types of drug delivery systems, such as Bioadhesive, Hyaluronic, Proliposomal, Osmotic drug delivery systems, are known in the art. One of the oldest forms, that has existed for of several centuries, for applying medicaments locally through patient's skin, and for applying medicines to the eyes and ears is Iontophoresis. It is also known to apply an electric field to the skin to greatly enhance the skin's permeability to various ionic agents. The use of Iontophoresis has helped to obviate the need for hypodermic injection and also it avoids the problems of trauma, pain and risk of infection to the patient.
A rich area of research over the past 10 to 15 years has been focused on developing transdermal technologies that utilize mechanical energy to increase the drug flux across the skin by either altering the skin barrier (primarily the stratum corneum) or increasing the energy of the drug molecules. These so-called "active" transdermal technologies include iontophoresis (which uses low voltage electrical current to drive charged drugs through the skin), electroporation (which uses short electrical pulses to create transient aqueous pores in the skin), sonophoresis (which uses low frequency ultrasonic energy to disrupt the stratum corneum). Even magnetic energy, coined magnetophoresis, has been investigated as a means to increase drug flux across the skin. Of these technologies, only iontophoresis has been successfully developed into a marketable product, albeit for local pain relief.
Most of the currently available form of transdermal drug delivery system uses a technique called drug-in-adhesive, which is used in patches like the nicotine patch.

"T2OD2", of the present invention, is a non-invasive means for providing continuous transcutaneous drug infusion to a patient, similar to intravenous administration, except that the drug is delivered from specially designed delivery port applied to the skin, which eliminates the need for vascular access and syringes or pumps. The major advantages provided by this kind of drug delivery technique include the following:
Improved bioavailability: avoidance of the first-pass metabolism by the liver as in the case of oral dosage forms.
More uniform plasma levels: controlled zero-order absorption through the stratum corneum into the systemic circulation so as to reduce periods of underdosing and oversdosing.
Longer duration of action: ability of the "T2ODr to adhere to the skin for as long as 7 days, resulting in a reduction in dosing frequency.
Reduced side effects: due to reduction of the peaks in plasma levels unlike what results from conventional oral dosage forms.
Improved therapy: due to maintenance of plasma levels up to the end of the dosing interval compared to a decline in plasma levels with conventional oral dosage forms.
Improved patient compliance: due to the reduced dosing frequency and reduction of system side effects.
Noninvasive dosing: elimination of local infection associated with subcutaneous, intramuscular or intravenous injections.
Reversible action: removal of the "T2OD2 " port can reverse and adverse effects due to overdosing.

Easily Available Drug forms: Drugs filled in soft capsule, similar to oral dosage forms can be adopted with minor changes for use in this invention.
Today pharmaceutical companies face two major problems. The patent protection for many established drugs are coming to an end and new biotechnology-derived products, namely peptides and proteins or even nucleic acids, are either metabolised when administered intravenously or broken down by the digestive system when delivered orally. Drug delivery is the field of research, which promises to solve these challenges.
The primary object of the present invention is to address the above issues. The present invention relates to a Drug Delivery System, which will be called "Transcutaneous Thermoelectroporic Omnimolicular Drug Delivery System (T OD )".
The present invention provides a system and a method of drug delivery that uses specialised thermal energy combined with high energy electroporation to first alter the skin barrier (stratum corneum, the topmost layer of the skin that serves as the greatest barrier to drug diffusion), and next to increase the energy of drug molecules. This way one can even transfuse macromolecules like insulin transcutaneously without the use of needles.
The A broad spectrum of potential applications of this invention can includes the following:
Immunology - where one envisions a single-shot vaccine delivery system capable of pulsatile dosing to immunise against multiple diseases
Oncology - where a protein such as an angiogenesis inhibitor is delivered locally at the tumor site
Gene therapy - where nucleic acid has to enter the cell nucleus

Tissue engineering - where growth factors are released from polymers at appropriate times to promote tissue regeneration
In Diabetic patients, who are insulin dependent, this invention will help them to live an almost normal life without injection's everyday. In cancer patients, who are already in pain, painkillers can be effectively given with least side effects and without pricking.
This invention will now be described with reference to the accompanying drawings, wherein: Fig. 1 illustrates the drug delivery system comprising the Control unit and Delivery port; and Fig. 2 illustrates the block diagram of the Control Unit.
The drug delivery system of the present invention consists of two parts, a control unit with the
0 0 0 0
necessary electronics and the delivery system called T OD -Port. The T OD -Port is a small device as shown in Fig. 1. This device is the interface between the control unit and the body.
_^ *^ .^_> O — _-0 — O
The T OD is strapped on the surface of the skin using a Velcro strap. The T OD - Port is completely coated with Gold of about 50-micron thickness, to avoid any reaction between the port and the skin and the port and the drug inside port reservoir.
The Control unit consists of the following major sub-systems:
1. User Interface and Keyboard
2. System Control Microcomputer
3. Pulse Modulation System
4. Power Supply Controller
5. Electropore Generator
6. Temperature Control System
7. Alarm and Safety Control.
User Interface and Key Board: User Interface and keyboard sub assembly consists of a numerical keyboard, to enable the user to input set-up information and a numeric display. Information like the molecular weight, delivery rate etc., are fed into the system from here.

System Control Microcomputer (SCM): This is the heart of the system, it contains all the algorithm to perform the complete function of the device. The SCM controls all the other sub-assemblies, it takes in the feed back information from the T OD port and processes the required pulse rates and temperature gradient.
Pulse Modulation System: The Pulse Modulation System or PMS accepts commands from the SCM and accordingly modulates the output pulses that are sent to T2 OD2 -Port's gold electrode, which depends on the various set parameters.
Power Supply Controller: The power supply controller controls and converts, 4.5v D.C from two batteries to the required power for all the subassemblies. Including the high voltage requirements of the device. It also controls and regulates the current, based on the requirements of the SCM.
Electropore Generator: The Electropore Generator is controlled by the SCM, it basically provides for the required e-pore pulsation based on the set programme and voltage and current set by the power supply controller. Electropore Generator is a high precision special pulse generator that actually creates microscopic pores into the different layers of the skin depending on the pre-set parameters.
Temperature Control System: Accurate temperature that varies in milli-degrees centigrade is an important aspect of this device. The temperature variations are from room temperature to about 40 degrees centigrade, with accuracy of 0.001 degrees. Precision temperature is what sets the required permeability of the skin, at the time of drug transfusion.
Alarm and Safety Control: Any such device that is used for critical application as delivering a life-saving drug should have utmost safety in its operation. Any thing in the operation of the system can go wrong, like the thermoregulatory system, or the electroporation system, which effects the performance of the device. It may even not transfuse the drug or it may change the dosage, while the user has no knowledge about it. This subassembly continuously monitors all the controls and other subassembly and itself for malfunction and any abnormality that is

encountered, the device is forced to shut down, even by bypassing the SCM. The subassembly provides alarms in the form of sound and blinking lights on the display of the device and indicating the exact nature of the problem encountered.
The delivery port comprises of a flat base 1 made of brass and is completely coated with gold of about 50-micorn thickness, to avoid any reaction between the port and the skin and the port and the drug inside the port. The said base 1 houses a drug compartment 2 with a cap 3 wherein the drug filled in the form of a capsule 4,or the like is placed. The base 1 also houses drug reservoir 5, having a permeable membrane 6, with a diffusion needle 7. The diffusion needle 7 projects into the drug compartment 2. The base 1 also has holders 8 for holding the gold electrodes 9 which are connected to the control unit 10 through the electropore circuit 11. A thermistor 12 is provided for measuring the temperature of the skin surface and feed it back to the controller to maintain the prescribed temperature. And a heat pulser 13 is provided for maintaining a pre-set temperature on the surface of the skin in a pulsed manner, which depends on the characteristics of the drug being delivered.
Usage;
The usage of the invention starts with the T2OD2 -Port fixed on the skin, various parameters are set using the control unit, like the molecular weight of the drug, rate of release of the drug and setting of any alarm conditions. Now the drug, which will be in a liquid form, filled in a soft capsule. The drug compartment cap 3 is opened and the capsule is deployed, and the lid 3 is closed. The closing of the lid will push the capsule, to be punctured by the diffusion needle 7. The environment in the drug reservoir 5, will start diffusing the drug towards the permeable membrane 6, by this time the stratum corneum, the top most layer of the skin is made porous using molar dependant electroporation increasing the permeability of the skin, and the infrared energy of the thermal pulsation would have accelerated the molecules of the drug. The drug now begins to transfuse through the different layers of the skin, until it reaches the blood stream that carries the drug further in the system. The pores created in the stratum corneum will be closed within 30 seconds after the device is switched off. The device is equipped with feedback systems, measuring the temperature, pulsation rate, voltages and currents and continuously makes alterations to suit environmental changes that may occur around the user.

I claim:
1. A transcutaneous, thermoelectroporic, omnimolicular drug delivery system comprising of a
control unit and a delivery port, the control unit comprises of an input device, a system
control microcomputer, a pulse modulation system, means to control power supply,
electropore generator, a thermostat and an alarm, the delivery port comprises of a drug
compartment with a lid, a drug reservoir having means for diffusing the drug to be delivered,
said means being placed in such a way to establish a connection between the drug
compartment and drug reservoir, electrodes for receiving the pulses generated by the
electropore generator in the control unit, means for holding the said electrodes, a heat pulser
and a thermistor.
2. The drug delivery system as claimed in claim 1, the means for diffusing the drug to be
delivered is a diffusion needle placed in the drug reservoir and projecting into the drug
compartment.
3. The drug delivery system as claimed in claim 2, wherein the input device is an user interface
and keyboard.
4. A method of drug delivery that uses infrared or thermal energy in combination with active
electroporation to transport or transfuse all kinds of drugs and chemical substances into the
human body through the skin route.
DATED THIS 17TH DAY OF SEPTEMBER 2005.

Documents:

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Patent Number

269849

Indian Patent Application Number

1330/CHE/2005

PG Journal Number

46/2015

Publication Date

13-Nov-2015

Grant Date

11-Nov-2015

Date of Filing

20-Sep-2005

Name of Patentee

DR. RAJAH VIJAY KUMAR

Applicant Address

AT S-CARD, CAMPUS SEEGAHALLI MAIN ROAD, VIRGONAGAR BANGALORE 560 049 KARNATAKA

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. RAJAH VIJAY KUMAR	AT S-CARD, CAMPUS SEEGAHALLI MAIN ROAD, VIRGONAGAR BANGALORE 560 049 KARNATAKA

PCT International Classification Number

A61K 48/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA