HK1153960B - Integrated intra-dermal delivery, diagnostic and communication system - Google Patents

Description

Integrated intradermal delivery, diagnostic and communication system

Cross Reference to Related Applications

The present application claims the benefit of U.S. patent application nos. 61/014,184 and 61/023,972, each of which is specifically incorporated herein by reference in its entirety.

Technical Field

The present invention relates generally to integrated intradermal delivery, diagnostic and patient interface systems, and more particularly to a transdermal delivery system having micro/nano features suitable for delivery below the stratum corneum, to an integrated biosensing system, an integrated microcontroller and an integrated communication system that can be used with the transdermal delivery system.

Background

The health care industry in the united states drives an annual health related cost of about $ 2 trillion. Goods and services are provided by the manufacturers of pharmaceuticals, medical devices and other supplies, which have a combined revenue of 3 billion dollars, and the providers of care, which have a combined revenue of 1.5 trillion dollars per year, doctors, hospitals, clinics, nursing centers, etc. The cost of most health care is subsidized by private health insurance companies, which subsidize approximately $ 7 billion per year, and government health insurance programs such as Medicare and Medicaid, which provide joint payments of $ 1 trillion per year. In the 1.5 trillion dollar care provider market, the Managed Healthcare (Managed Healthcare) segment accounts for approximately 3 billion to 5 billion dollars.

This segment of the industry offers various types of health insurance plans designed with ways to control the costs of health care related costs. The main products include health maintenance organizations (HMO's), preferred healthcare organizations (PPO's), point of service plans (point of services plans), and guaranteed benefit plans (indemnity beneficiary plans).

The industry has expanded over the past decade, provided that traditional methods of delivering healthcare are financially wasteful. Managed care companies attempt to control costs from four aspects: minimizing care usage by providing financial incentives to providers and users, contracting for services at discounted rates, reviewing expenses to determine the legitimacy of expenses and establishing low-cost treatment agreements that providers are expected to comply with. They are an effective, regulatory intermediary between providers and users of healthcare.

In addition to using financial incentives to limit non-essential medical care, managed health care companies use "utilization management" to review and standardize care. A committee of doctors and administrators reviews actual services used in the network to determine whether they are being used properly and recommends standards of care that doctors and hospitals are expected to comply with. The committee also determines drug prescription schedules that specify which drugs are to be used to treat a particular condition. The statistics collected for utilization in management can also be used in risk management and insurance, the process of determining what consideration is paid to the provider and what premium is paid to the consumer. Computerized information and communications systems are important to managed healthcare companies in processing claims and managing records and statistics collection and analysis.

A series of opportunities that appear to have not yet been developed are preventive care and rehabilitation process management. According to the perpetual principals of Pricewale (PricewaterfouseCoopers), preventative care and disease management programs have the undeveloped potential to enhance health and reduce costs, which is beneficial to managed care and consumers.

Delivering care involves a complex interrelationship between multidisciplinary providers of various services and products. The possibility of waste is common. The interviewees of the HealthCast 2020 survey say that sustainability relies on motivating clinicians, hospitals, pharmaceutical companies and payers together to integrate care and manage chronic diseases. The applicant believes that there is another key component in this complex series of relationships, namely the patient. Compliance with health, prevention and treatment regimens eventually begins with the patient and ends with the patient. Patients are notoriously ineffective in maintaining compliance with their treatment regimen. Effectively integrating delivery, diagnosis and communication into a single patient-friendly system is expected to significantly improve patient treatment outcomes while reducing costs and improving profitability for healthcare providers.

The best pharmaceutical dosage form for achieving the above-described integration of functionality and technology is a patch or transdermal system. Currently available patches and transdermal technologies do not have these properties and there is a need for improved products that address and overcome these deficiencies.

Transdermal drug delivery systems are systems that deliver a dose of drug through the skin for local or systemic distribution. The system often promotes healing of a particular injured area of the body. Transdermal drug delivery systems have the advantage of providing controlled release of the drug to the patient compared to other types of drug delivery systems, such as oral, topical, etc. A wide variety of drugs may be delivered by transdermal drug delivery systems.

One common transdermal drug delivery system is the transdermal patch. A typical transdermal patch includes the following: (1) the inner liner of the protective patch is removed during storage and prior to use; (2) a drug solution in direct contact with the release liner; (3) an adhesive for adhering the parts of the patch together and for adhering the patch to the skin; (4) a membrane to control release of the drug from the reservoir and the multilayer patch; and (5) a backing to protect the patch from the external environment.

There are at least four different types of transdermal patches. One type is a single layer drug-containing adhesive, where the adhesive layer of the system also contains a drug. The adhesive layer is surrounded by a temporary liner and a backing. The second type is a multi-layer drug-containing adhesive, where both adhesive layers are also responsible for drug release; however, in this system, another layer of drug-containing adhesive is added. The patch also has a temporary inner liner and a permanent backing. A third type of patch is the reservoir type, having individual drug layers that are liquid or semi-solid compartments separated by adhesive layers containing drug solutions or suspensions. A fourth type of patch is a matrix system having a semi-solid matrix drug layer containing a drug solution or suspension. The adhesive layer surrounds the drug layer, partially covering it.

These passive systems are limited in that they are generally only effective in delivering (i) low molecular weight (< 500Da) compounds, (ii) lipophilic compounds, and (iii) compounds that require low doses (20-25mg) to be effective.

SUMMARY

According to one embodiment of the present invention, an intradermal delivery, diagnostic and communication (IDDC) system utilizes a smart therapeutic agent delivery system that includes at least one "cell", but more likely an array of "cells", containing a therapeutic and/or diagnostic agent. The IDDC system also includes an integrated biosensing system designed to collect and analyze biological material to measure and determine a number of parameters, including but not limited to: i) clinical or therapeutic markers or substitutes thereof, e.g. blood pressure, blood or interstitial glucose levels, histamine levels, cholesterol levels, triglyceride levels, etc., ii) circulating levels of therapeutic agents, using a multiplex sensor comprising both a hardware part and a software part, wherein the software part comprises biomedical signal processing and/or pattern recognition for analyzing complex liquid mixtures, etc. The IDDC system also includes at least one microcontroller that interfaces the biosensors, therapy delivery elements, and communication systems for the purpose of controlling the amount of therapeutic agent delivered and providing information about the progress of therapy and compliance with therapy to the relevant parties (patient, physician, managed care organization) in a useful form.

A communication system may be provided to manage the collection, storage and transmission of information from the above systems to a receiving system, which may include ubiquitous communication devices such as cell phones, PDA's and infrastructure services such as WiFi, WiMax, cell towers (cell towers) and the like, another role of the communication system being the initial configuration and ongoing modification of the therapeutic agent delivery regimen (maximum dose per unit time, etc.). An energy storage and delivery subsystem (subsystem) is also included as part of the IDDC system, the purpose of which is to provide power stored in batteries, capacitors, to other subsystems of the device, which is transmitted via communication lines including, but not limited to, radio lines, radio frequency (rf) links, or combinations thereof. The synergy combined with the above elements significantly increases the likelihood of patient compliance with prescribed therapy, the quality and timeliness of care provided by physicians, while reducing the cost of providing effective health care to IDDC system users, thus increasing the profitability of managed care organizations and pharmaceutical companies utilizing the present system.

In one embodiment, an intradermal delivery, diagnostic and communication (IDDC) system includes a drug-containing micro/nano-sized chamber that stores at least one drug, therapeutic agent, etc. within a membrane of the chamber. The chamber also has a magnetic element associated therewith. The system also includes a drug delivery device in the form of a micro/nano-lancet having a drug delivery channel defined with an inlet and an outlet, the outlet being defined at the sharp distal end of the lancet. The lancet also has an actuator, such as a magnetic or piezoelectric element associated therewith. At least one magnetic or piezoelectric element is an element that is energized by a power source. Upon energizing the electromagnetic or piezoelectric element, the lancet is driven forward through the drug-containing chamber such that the drug or therapeutic agent in the membrane flows into the inlet, through the lancet to the outlet, where it flows out into the body below the patient's stratum corneum. After successful delivery of the drug or medicament, the lancet can be removed by de-energizing the magnetic or piezoelectric element. Alternatively, the electromagnetic or piezoelectric element may be energized with a reverse polarity to withdraw the lancet.

In another embodiment, a micro/nano implant device includes a body having support posts and magnetic or piezoelectric elements. A micro/nano barbed implant with drug or agent incorporated therein is held at one end (opposite the magnetic element) of the support post. The magnetic membrane is placed along the skin of the patient and by energizing the magnetic or piezoelectric elements, the barbed implant and the support posts penetrate the stratum corneum and the implant is placed at the desired depth under the skin. When the magnetic or piezoelectric element is de-energized, the device may be withdrawn from the stratum corneum; however, the barbs of the implant bite into the skin layer, thereby retaining the implant at the desired location and depth beneath the patient's skin.

In another embodiment, a micro/nano-implant device includes a body having support posts supported by a first side of a base layer. A micro/nano barbed implant with a drug or agent incorporated therein is held at one end of the support post (opposite the substrate). The barbs are recessed or otherwise contained within the surrounding flexible material. The substrate is placed on the skin of the user with the barbs and the flexible material facing the skin. Pressure applied to the opposite second side of the substrate causes compression of the flexible material, allowing the barbs to be implanted through the stratum corneum to a desired depth beneath the skin, which generally corresponds to the height of the barbs from above the substrate. The barbs remain in the skin after the substrate is removed. The barbs are bioabsorbed over time. The flexible material may be incorporated into the skin contact layer, including local anesthetics, which may be from but not limited to benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine (Alcaine), proxymetacaine, and tetracaine (also known as amethocaine), which are incorporated into the adhesive layer, which may be composed of a cross-linked polymer or other material, preferably some inert substance such as silicon dioxide.

In another embodiment, the microneedles with channels are mounted on an oscillating movable base. Contact between the device surface and the skin is handled and limited by the stationary housing. The microneedles oscillate at a frequency of about 0kHz to about 3MHz (preferably at about 5kHz to about 2MHz) with an amplitude of about 0 to about 1000 microns (preferably at about 5 microns to about 250 microns). The amplitude of the oscillation differs based on drilling/opening of channels and/or pumping/sucking of drugs/blood/interstitial fluid in the Stratum Corneum (SC)/epidermis/dermis layers. The oscillating microneedles (relative to the fixture casting) create holes in the stratum corneum with defined properties. The design of the microneedles varies based on the specific requirements and depends on the particular application. Back pressure and/or stratum corneum-device interface pressure drive the drug to a target level in the intradermal space. Negative back pressure (difference) is used to draw blood and/or interstitial fluid from the intradermal region into the appropriate reservoir and into contact with the sensor. Pressure fluctuations and motion control are used to move liquid into and out of the reservoir and into and out of contact with the sensor. The pressurized reservoir uses a synchronization scheme. The frequency and duty cycle and synchronization are optimized for maximum performance. Biological samples can be obtained using a variety of different techniques, including manipulating the device to remove a sample therefrom when a pressure differential is created within the device.

Biosensing of biological materials can be achieved by using electrical/electrochemical detection. The system may utilize one or more of the following: i) measuring a direct current response (amperometry), ii) measuring a direct current response (potentiometry), using a direct current, or iii) measuring an alternating current response (capacitance or impedance), using an alternating voltage. In all cases, three electrodes: the working, reference and counter electrodes are incorporated into an intradermal delivery, diagnostic and communication device. The electrodes are placed as close together as possible and analyte detection occurs at the working electrode. Ideally, the electrodes are designed so that a voltage is applied between the working and reference electrodes and a current is detected through the counter electrode.

Additional embodiments include the use of an electrode array, sometimes referred to as an "electronic tongue," for subtracting signals from the background or interfering species from the analyte of interest. The electronic tongue includes hardware and software that allows for accurate transcutaneous or intradermal detection of analytes in blood or interstitial fluid. The hardware of the electronic tongue is an array of sensor electrodes on which a clear electrical/electrochemical signal can be obtained. Individual electrodes are constructed of different materials, coated with different membranes, or have different biomolecules immobilized on or near their surfaces. As described above, each individual sensor electrode may be detected using amperometric, potentiometric, capacitive or resistive. For electronic tongues, the reference electrode is sometimes shared by multiple working electrodes. The software of this type of system utilizes the electrode array to identify relevant patterns of the analyte of interest. By using an array of electrodes, a "pattern" that is more robust to selectivity problems can be detected with respect to any individual electrode.

For larger molecules that elicit an immune response, antibody electrodes can be used to construct electrochemical immunosensors that can also be subject to interference from other species than the analyte of interest. Some U.S. patents, including U.S. patent nos. 7,241,628, 7,241,418, 6,815,217, and 5,356,785 (each of which is incorporated herein by reference in its entirety), describe methods using reference channels to subtract out the effects of interfering species in sensors for antibodies, DNA, and nucleic acids; however, all of these methods suffer from interference from non-specific interactions and cross-reactivity and, therefore, have limitations and disadvantages.

Although these patents discuss the use of reference antibodies, nucleic acids and DNA to subtract out the signal of interfering species, the patents discuss optical, not electrical/electrochemical methods, and none of these patents mention intradermal or transdermal applications. The use of ULSI sensor devices allows more sophisticated approaches to background subtraction, including electronic tongues built with electrochemical sensor arrays.

The hardware of the electronic tongue also includes interface circuitry that allows for an interface between the microcontroller and the individual sensors. The interface circuit allows for individual reading of the signal from each sensor in the array, allows for signal conditioning for translation of the signal level to a level interpretable by the microcontroller, and allows for digitization of the sensor signal for further processing by a software element.

The software components of the electronic tongue include analysis of the signal collection from the sensor electrode array by signal processing and pattern recognition algorithms. Pattern recognition methods are applied to the signals obtained by the sensor array for a large sample of blood and/or interstitial fluid. This huge data set is analyzed off-line to develop a pattern recognition algorithm that is recognized by a consolidated processor or an integrated processor wirelessly transmitted to the outside to find patterns that allow subtraction of the signal of background or interfering species from each sensor electrode, allowing detection of only the species that each electrode is designed to detect. When an antibody or oxidoreductase is immobilized at or near a particular sensor electrode, the electrode is designed to detect a particular corresponding analyte. Typically, the electronic tongue may also contain blank sensor electrodes that are only present for background subtraction when using the pattern recognition algorithm.

Furthermore, pattern recognition may be performed by a combined processor or wirelessly transmitted to an external integrated processor. Supervised pattern recognition algorithms such as support vector machines (support vector machines), logistic regression (logistic regression), neural networks (neural networks) may be used and include the steps of preprocessing, feature extraction, and classification training. The huge data set is used to train algorithms to recognize complex patterns. The readout data is processed by the on-board electronic controller. The processed data and instructions are transmitted to and from the patient, physician and/or health care provider via wireless communication.

The software element measures the amount of interest (biomarker concentration) stored internally or reported by the communication subsystem, or determines the presence of an event of interest (e.g., a normal concentration of a certain biomarker as described above), which may trigger delivery of a therapeutic agent or report event detection by the communication subsystem. If local processing and local delivery on a combined processor (microcontroller), the processor executes an algorithm of the software elements, determines the presence of an event of interest, and delivers a therapeutic agent if needed. If remote processing by the software component of the biosensor data, the microcontroller receives the results over the wireless interface and then makes delivery decisions. Optionally, the detection of the event of interest is communicated to the user, who then makes a decision on the delivery of the therapeutic agent, which is communicated to the microcontroller via the wireless interface. By activating the delivery subsystem, the microcontroller initiates drug delivery.

It will also be appreciated that channeled microneedles, microchannels, suction devices with controls, valves, pressure/motion actuators (acoustic, electrical, etc.), reservoirs, dump sites (reservoirs), sensors (for biomarkers, etc.), ultrasound (low and high frequency), sonophoresis, shock (bending waves), heat (thermophoretic), heating, combustion, thermal oscillation, thermal skin/osmosis), iontophoresis (electric field, polar molecule migration), electric pulses (electromagnetic field), electroporation, magnetophoresis (magnetic field), and chemical permeation enhancers may be used.

Functionality is achieved when the repeated pulsing of the needle creates a high pressure field in the orifice of the dermal layer for drug delivery due to reservoir pressure and/or inertial/kinetic effects. To extract blood/interstitial fluid, the back pressure is reduced. The reservoir pressure oscillates and synchronizes with the needle oscillation to improve pumping.

It should be appreciated that the systems and devices of the present invention can be used to deliver a variety of different types (classes) of drugs, as described herein. For example, the following drug classes and drugs are exemplary and can be incorporated into one or more of the devices and/or methods disclosed herein in accordance with the present invention: cardiovascular and inotropic drugs (e.g., cardiac glycosides); antiarrhythmic drugs (e.g., quinidine); a calcium channel blocker; vasodilators (e.g., nitrates and peripheral vasodilators); anti-adrenergic/sympatholytic agents (e.g., beta-adrenergic blockers, alpha/beta-adrenergic blockers, anti-adrenergic-central effects, anti-adrenergic-peripheral effects/alpha-1 adrenergic blockers); antagonists of the renin angiotensin system (e.g., angiotensin converting enzyme inhibitors, angiotensin II type receptor antagonists); an antihypertensive combination; pheochromocytoma drugs; a hypertension risk drug; antihyperlipidemic drugs (e.g., bile acid sequestrants, HGM coa reductase inhibitors, fibric acid derivatives); vasopressors used in shock; a potassium removal resin agent; edetate disodium; cardioplegic solution; patent ductus arteriosus drugs; a hardening agent; endocrine/metabolic; sex hormones (e.g., estrogens, selective estrogen receptor modulators, progestogens, ovulation stimulants, gonadotrophins, including gonadotropin-releasing hormone, gonadotropin-releasing hormone antagonists, androgens, androgen hormone inhibitors, protein anabolic steroids); uterine active agents (e.g., abortifacients, cervical ripening agents); a bisphosphonate; antidiabetic agents (e.g., insulin, high potency insulin, sulfonylureas, alpha-glucosidase inhibitors, biguanides, meglitinides, thiazolidinediones, antidiabetic combinations); a glucose-raising agent; corticosteroids (e.g., adrenal steroid inhibitors, adrenocorticotropic hormone, glucocorticoids, glucocorticoid/corticosteroid retention enemas, glucocorticoid/corticosteroid intrarectal foams, mineralocorticoids); thyroid drugs (e.g., thyroid hormones, antithyroid agents); growth hormone (e.g., posterior lobe hormone, octreotide acetate); imiglucerase (imiglucerase); salmon calcitonin; imiglucerase; sodium phenylbutyrate; anhydrous betaine; cysteamine bitartrate; sodium benzoate/sodium phenylacetate; bromocriptine mesylate; cabergoline (cabergoline); gout drugs (e.g., uricosuric drugs); antidotes (e.g., narcotic antagonists); a respiratory medicament; bronchodilators (e.g., sympathomimetics and diluents, xanthine derivatives, anticholinergics); leukotriene receptor antagonists; leukotriene formation antagonists; a respiratory inhalant product; a corticosteroid; intranasal steroids; mucolytic drugs; mast cell stabilizers; respiratory tract gases; nasal vasoconstrictors (e.g., aromatic alkylamines and imidazolines); a respiratory enzyme; a pulmonary surfactant; an antihistamine; alkylamines, non-selective; ethanolamine, non-selective; phenothiazine, non-selective; piperazine, non-selective; piperidine, non-selective; phthalazinone (phthalazinone), peripherally selective; piperazine, peripherally selective; piperidine, peripherally selective; a combination medicine for relieving asthma; a combination drug for the upper respiratory tract; a cough preparation; renal and genital medications; interstitial cystitis medicine.

Some suitable drugs falling within the above categories include Rosiglitazone (Rosiglitazone), interferon alpha 2b, Omalizumab (Omalizumab) (sorel, Xolair), Cetirizine (Cetirizine), Erythropoietin (EPO), and metoprolol (metoprolol) tartrate. In general, a variety of different protein drugs can be delivered using the system of the invention. In addition, the systems and devices of the present invention may use a variety of different biomarkers depending on the drug of interest. For example, some biomarkers of interest include, but are not limited to, glucalanine, hepatitis C virus, immunoglobulin E, histamine, ferritin, transferrin, and C-reactive protein. Thus, it will be appreciated that the biomarker is selected in view of the drug selected for delivery or the disease selected for monitoring.

In addition, the present invention provides significant improvements over conventional systems, including the use of an electronic tongue in which a signal processing algorithm is applied to an array of electrodes to subtract out background or interfering signals. In particular, conventional systems do not use antibodies immobilized on electrodes, and in addition, conventional systems do not use capacitive or impedance detection, both of which involve alternating current signals, rather than direct current signals.

The use of "electronic nose" is known, which is similar to the electronic tongue concept described above. However, the electronic nose is designed to detect gas phase species. In accordance with the present invention, detection of particulate matter in the gas phase or at least airborne can be incorporated into the present system in the event that the user wishes to control a biological response and/or drug delivery based on signals from the surrounding environment using a device as described above. In this case, the signal does not originate from a liquid medium, but from a gaseous or atmospheric medium (e.g. ambient signals from pollen in the atmosphere). The electrodes and electrical/electrochemical methods used in this case are selected and designed based on the location of origin of the ambient signal (e.g. gaseous or atmospheric medium).

Brief description of the drawings

The foregoing and other features of the invention will be more readily understood from the following detailed description of exemplary embodiments of the invention and the accompanying drawings.

FIG. 1 is a side cross-sectional view of a micro/nano drug-containing membrane or cell, according to one embodiment of a transdermal delivery system;

FIG. 2 is a side cross-sectional view of a micro/nano drug delivery device for use with the cell of FIG. 1;

FIG. 3 is a side cross-sectional view of the drug delivery device in proximity to the chamber prior to drug delivery;

FIG. 4 is a side cross-sectional view of the drug delivery device inserted into the skin of a patient after engaging the chamber to deliver a drug to the patient;

FIG. 5 is a side cross-sectional view of a micro/nano implant in accordance with another embodiment of a transdermal delivery system;

FIG. 6 is a side cross-sectional view of a micro/nano implant according to another embodiment;

FIG. 7 is a side cross-sectional view of a micro/nano implant according to another embodiment;

FIG. 8 is a side cross-sectional view of a micro/nano implant according to another embodiment;

fig. 9 is a top plan view of an array of micro/nano drug delivery devices as part of a transdermal delivery system;

FIG. 10 is a side cross-sectional view of an array of micro/nano barbed implants;

FIG. 11 is a schematic diagram of a biofeedback system;

FIG. 12 is a side cross-sectional view of a micro/nano barb assembly with a protective glue coating;

fig. 13 is a side cross-sectional view of an applicator for use with a micro/nano drug delivery device, including the one in fig. 12;

FIG. 14 is a cross-sectional view of an alternative micro/nano drug delivery device for use with the chamber of FIG. 1;

fig. 15 is a cross-sectional view of an alternative micro/nano drug delivery device according to another embodiment;

FIG. 16 is a cross-sectional view of an alternative micro/nano needle in accordance with another embodiment;

fig. 17 is a cross-sectional view of an alternative micro/nano drug delivery device according to another embodiment;

fig. 18 is a cross-sectional view of an alternative micro/nano drug delivery device depicting an oscillating motion and associated pressure differential, in accordance with another embodiment;

FIG. 19 is a schematic diagram of a drug delivery device connected to a biosensor, control system hardware and a communication unit;

fig. 20 is a cross-sectional view of an alternative micro/nano drug delivery device depicting pressure and motion actuators;

fig. 21 is a cross-sectional view of an alternative micro/nano drug delivery device depicting a piezoelectric element;

fig. 22 is a cross-sectional view of an alternative micro/nano drug delivery device depicting the biosensor interfacing with the drug delivery subunit and control system.

Description of The Preferred Embodiment

For some applicants, the best transdermal delivery system is a topical patch, gel, cream, or similar applied system that can be easily applied by the patient or caregiver in a convenient but unobvious location. The system delivers its target drug, which may be a small molecule or a biological agent, at a predictable and programmable rate and absorption kinetics. In one form, the system may be designed to deliver drugs to achieve local or regional effects. In other embodiments, the system may be designed to achieve predictability of intravenous infusion without suffering and the inconvenience of having a port installed. The system should be designed to produce only a storage effect. In addition, the drug release kinetics should not be disturbed by normal use and should be difficult to deliberately perturb. The duration and extent of delivery is controlled by a combination of release site, release rate and surface area. The objective is to provide controlled delivery from a one-day application up to and including 10-day treatment to accommodate most antibiotic prescription regimens. It is to be appreciated and understood, however, that the life span of the delivery system described herein varies depending on the situation requiring treatment. For example, the device is designed for use as part of a chronic treatment, and thus, depending on the conditions and application, a controlled delivery from the day until the end of human life may be achieved. Thus, the time periods and treatment lengths described above are exemplary only and not limiting.

The above objects are accomplished, in accordance with one embodiment of the present invention, by an intradermal delivery, diagnostic and communication system 100 as shown in FIGS. 1-4. The system 100 is of the type that includes one or more drug reservoirs or reservoirs and includes means for delivering the drug to the patient. The system 100 includes at least one drug-containing member 110 that stores the drug to be delivered. The member 110 includes an actuator 112 that may be in the form of a magnetic film composed of a magnetic material, and a drug-containing cell 120 (other actuators may be used, such as piezoelectric-based actuators, and therefore, the discussion herein of the magnetic film 112 is intended to encompass one embodiment, and not to limit the invention, as the actuator 112 may be other types of actuators). The drug-containing chamber 120 is flexible but provides the necessary stability to provide a drug-containing chamber, which may be in the form of a drug solution or suspension. The drug containing chamber 120 is thus interpreted as an internal pocket or compartment (component) containing and storing the drug to be delivered. Also, where the term "drug" is used herein, it should be recognized that substances other than drugs may be stored in the chamber. For example, the chamber may contain therapeutic agents, vitamins, etc., and is not limited to substances classified as "drugs" according to applicable government guidelines.

As shown in fig. 1, the magnetic thin film 112 is disposed on the cell 120. The shape and size of the cell 110 may be designed according to the intended application, including the type of drug to be delivered and the amount to be delivered over time.

Drug delivery system 100 further includes a drug delivery device 130, drug delivery device 130 being complementary to drug containing member 110 and designed to mate with member 110 for controlled delivery of the drug contained in chamber 120. For example, drug delivery device 130 may be in the form of a mechanically robust micro-or nano-lancet or the like as a carrier inlet and cell seal. The lancet 130 includes a first end 132 and an opposing second end 134. At the first end 132, the lancet 130 has a magnetic contact 140. The magnetic contact 140 may be in the form of one or more pads or other type of structure. In the illustrated embodiment, the lancet 130 has a support structure 134 (flat surface) that supports a magnetic contact 140.

The lancet 130 also has an elongated hollow body 150 through which the drug is delivered 150 as described below. The hollow body 150 may be an elongated tubular structure (cylindrical tube) having an inlet 160 (drug inlet or orifice), the inlet 160 being formed between the first and second ends 132, 134 and located on one side of the hollow body 150. In other words, the hollow body 150 includes a main hole 152 and an inlet 160 formed perpendicular to the main hole 152. The second end 134 represents the open end of the hollow body 150 and thus represents the distal opening 135 of the main bore 152. The distal opening 135 at the tip 134 serves as a drug delivery orifice or outlet. It will be appreciated that the second end 134 of the lancet 130 is a sharp end that allows the lancet to penetrate an object, such as a patient's skin. The second end 134 is thus a sharp, beveled edge.

The lancet 130 also includes a bias member 170 disposed between the hollow body 150 and the support structure 134. After delivery of the drug from the chamber 120, the bias member 170 moves the lancet 130 relative to the drug containing member 110. In the illustrated embodiment, the biasing member 170 is in the form of a spring, such as a leaf spring, that is attached to the bottom of the support structure 134 and is externally crimped into contact with the hollow body 150 at a location approximately adjacent the inlet 160 so that the biasing member 170 does not impede the flow of medication into the inlet 160.

This configuration will thus store energy when the biasing member 170 is compressed as shown in fig. 4 and described below. As an alternative to biasing elements, if desired, spaced electromagnets may be energized to have an attractive force and thereby compress the gap therebetween, and thereafter energized to repel each other, if desired, thereby restoring the size of the gap therebetween.

According to one embodiment and as shown in fig. 3, the distance X corresponds approximately to the stratum corneum, which is the outermost layer of the epidermis (the outermost layer of the skin). It is composed mainly of dead cells lacking nuclei. The thickness of the stratum corneum varies according to the degree of protection and grip required for the area of the body. For example, the hand is typically used to grip an object, requiring the palm of the hand to cover a thick stratum corneum. Similarly, the sole of the foot is vulnerable to injury and is therefore protected by the thick stratum corneum. Typically, the stratum corneum contains 15 to 20 layers of dead cells.

In accordance with one method of the present invention, the sequence of administering one or more drugs to a patient using system 100 is as follows: first, an appropriate drug containing member 110 is selected according to the needs of the patient and then positioned so that the drug containing chamber 120 is positioned facing and in contact with the target site on the skin of the patient to which the drug is to be administered. Thus, it should be appreciated that the magnetic film 112 faces away from the patient's skin. The drug delivery device 130 is then placed so that the second end 134 faces the magnetic film 112. In other words, as shown in fig. 3, the sharp-penetrated end of the lancet 130 faces the drug-containing member 110, and fig. 3 is an illustration of the present system prior to administration of the drug to the patient.

Next, the magnetic elements, i.e., the magnetic film 112 and the magnetic contactor 140, are energized using conventional techniques. For example, the microprocessor may include circuitry for energizing the magnetic film, or other electrical components (e.g., capacitors) may be used to energize the two magnetic elements. The energized magnetic elements 112, 140 close the gap between them, causing the sharp second end 134 of the lancet 130 to first penetrate the first magnetic film 112 and then penetrate both the upper and lower surfaces of the cell or membrane 120. The magnetic elements 112, 140 contact each other as shown in figure 4, with the second end 134 of the lancet 130 located just below the bottom surface of the cell 120.

At least one magnetic element is an electromagnet; the other may be a permanent magnet or a layer of permanent magnets. The magnet system is energized when there is an energizing signal to drive both electromagnets, or when there is an energizing signal to drive one electromagnet adjacent to a permanent magnet.

The construction of the lancet 130 allows the drug in the cell 120 to be delivered to the patient therethrough, and more specifically, the dimensions of the lancet 130 and the cell 120 are selected such that when the magnetic elements 112, 140 are in contact with each other (fig. 4), the drug inlet 160 is located inside the cell 120 itself, allowing the drug contained therein to flow through the inlet 160 into the main bore 152. The medicament then flows in the direction of the arrows shown in fig. 4, flowing down the inlet 160 to the main bore 152 until exiting the outlet of the second end 134 into the patient. As mentioned above, the length of the lancet 130 is selected so that the second end 134 is at a desired penetration depth.

Thus, pressure from the lancet 130 applied to the drug containing member 110 forces the drug in the chamber 120 to flow into the main bore 152 and into the target tissue.

Also, because the lancet 130 pierces the drug containing member 110, the bias member 170 (if provided) compresses and stores energy.

At least one of the magnetic elements 112, 140 can be de-energized to allow the lancet 130 to be unconstrained and moved relative to the drug-containing member 110, and also to allow the biasing member 170 to release its energy back to a relaxed state. This process causes the lancet 130 to withdraw from the stratum corneum.

It will also be appreciated that the magnetic elements 110, 140 may be energized multiple times, e.g., sequentially, which may result in a pumping action to ensure that an optimal amount of the drug in the chamber 120 is delivered into the patient's skin.

The overall system 100 includes both macro-scale and micro-scale elements. For example, the elements of the system disposed within the body are built at the micro/nano scale to facilitate drug delivery to the patient in an unobtrusive manner; however, in certain embodiments, the structures, e.g., pathways, into which the microscale elements are incorporated are macroscale. When the system 100 is incorporated into a transdermal patch or the like, the means for adhering the system to the skin must be hypoallergenic and substantially robust enough to withstand normal daily functions, including hygienic activity, participation in sports, sleep, and the like.

Fig. 5 shows an intradermal drug delivery system 200 in accordance with another embodiment. System 200 is similar to system 100 in that system 200 utilizes a similar lancet design to produce a micro/nano implant for delivery into a patient. In this embodiment, system 200 includes an implant device 210 that includes a support structure having a base 212 at a first end 214 and an elongated support post 216 extending outwardly from a bottom surface of base 212. The base 212 may be formed of a flat surface with the support posts 216 oriented perpendicular to the base 212. Implant device 210 broadly refers to any type of device that may be implanted in a patient (e.g., a member capable of intradermal installation).

The system 200 also includes a magnetic element 220, which may be in the form of a magnetic sheet, the magnetic element 220 being coupled to the base 212. For example, the magnetic element may be a flat thin layer of magnetic material mounted on and attached to the upper surface of the base 212. Thus, the magnetic element 220 represents one end of the implant device 210.

Similar to system 100, implant device 210 can include biasing member 170. In the illustrated embodiment, the biasing member 170 is in the form of a spring, such as a leaf spring, that is attached to the bottom surface of the base 212, curves outward, and contacts the support post 216. Alternatively, the magnetic system arrangement may be used as described above to compress and restore the dimensions of the system 200 before and after placement of the implant into the skin.

The system 200 also includes a drug carrying element 230, in this case, the drug carrying element 230 is in the form of a micro/nano implant with barb structures 232. As shown in fig. 5, the implant 230 is attached to the second end 215 of the support post 216. The implant 230 has one or more barbs 232 and terminates in a sharp tip 234, the sharp tip 234 being intended to penetrate the patient's skin.

The system 200 further comprises a magnetic film 240 intended for placement on the skin of a patient. Thus, the magnetic film 240 may be a flat magnetic layer (sheet) that may be placed against the skin of a patient at the target site to be administered. To hold the magnetic film 240 in place on the patient's skin, the magnetic film 240 may include an adhesive or the like, such as an adhesive edge for temporarily adhering the magnetic film 240 to the skin.

It should be appreciated that in this design, the implant 230 is the member that carries the drug to be administered to the patient's body. The implant 230, including the barbs 232, may be constructed of many different materials, including a polymer matrix with biodegradable properties. Additionally, the implant 230 should be imperceptible when placed in the correct position, and non-hypoallergenic, with a predictable disintegration time period, wherein the rate of disintegration controls the rate of drug release because the drug is incorporated into the implant material. Alternatively, the implant 230 may be comprised of an absorbable polymer matrix, wherein the release rate is independent of the absorption rate, and absorption occurs after delivery of the drug contents.

The system 200 operates in the following manner to deliver medication to a patient. First, the magnetic film 240 is placed on the patient's skin and the implant device 210 is placed as shown in FIG. 5 with the implant body 230 facing the magnetic film 240. The magnetic element 220 and the magnetic membrane 240 are energized, thereby causing the magnetic elements 220, 240 to close the gap between them, resulting in painless penetration of the stratum corneum by the device 210, including the support post 216 and the implant 230. The biasing member 170 compresses and stores energy.

When the magnetic elements 220, 240 are adjacent to each other, the implant 230 is delivered to the desired penetration depth. The magnetic elements 220, 240 are de-energized, releasing the implant device 210 and allowing the biasing member 170 to release its stored energy, returning to its relaxed position, thereby withdrawing the base 212 and support post 216 from the stratum corneum. Upon withdrawal, the barbs 232 of the implant 230 bite into the skin surface, causing only the support post 216 to be withdrawn from the patient. This results in the implant 230 being left in the desired location and at the desired depth. The size of the implant 230 and the size and location of the barbs 232 are selected to accomplish this and to leave the implant 230 and the drug therein in place in the patient's body.

Fig. 6 illustrates another embodiment of a barbed implant, and more particularly, an implant 300 is shown for use with system 200. Implant 300 is similar to implant 230 in that it includes barbs 302; however, in this embodiment, the implant 300 has a drug-containing reservoir 310 formed therein. The reservoir 310 may be a simple hole formed therein that opens only at the first (top) end 304 of the implant 300.

The implant 300 and barbs 302 are made of a bioabsorbable material that is shaped to include a reservoir 310 that includes a material containing a liquid, semi-solid, or solid drug. The reservoir 310 is sealed to seal the medicament in place with a sealing membrane 320, the sealing membrane 320 extending across the open end 304 of the body 300. The sealing film 320 may be composed of a material that permeates or dissolves.

The dissolution rate of the carrier (small or large molecules), the surface area of the reservoir opening and the rupture/disintegration of the posterior membrane control the release rate of the drug.

Fig. 7 shows an implant 330, the implant 330 being composed of a solid or porous matrix and including a support post cavity (hole) 332 for receiving a support post 216 (fig. 5). The disintegration/dissolution of the matrix in the interstitial fluid controls the release rate.

In any of the above embodiments, the shape of the barb may be any that allows for imperceptible penetration and has sufficient trailing side to prevent the barb from backing out of the skin.

Fig. 8 shows another embodiment in which an implant 340 has a drug-containing reservoir 350 formed therein. The reservoir 350 may be a simple hole formed therein that opens at a first (top) end 352 of the implant 340 and at or near a second end 354 of the implant 340. The reservoir 350 is sealed to seal the medicament in place in the reservoir 350 by a first sealing membrane 360 and a second sealing membrane 362, wherein the first sealing membrane 360 extends across the open first end 352 of the body 300 and the second sealing membrane 362 extends across the open second end 354. The sealing films 360, 362 may be composed of a permeable or dissolvable material.

Fig. 9 illustrates a drug delivery system 400 in the form of an array of a plurality of drug delivery devices 410, which drug delivery devices 410 may be activated/triggered based on a prescribed time or response signal. For example, the system 400 may be connected to an energy source 420 that includes a time series firing mechanism. In other words, each individual drug delivery device 410 is connected to the energy source 420, and the controller (microprocessor) can be programmed as required by the patient to sequentially fire a prescribed number of drug delivery devices 410 over a period of time to deliver the drug at set time intervals and for that period of time. It should also be appreciated that the array may include more than one drug, where some drug delivery devices 410 may contain one drug while others contain other drugs. By connecting each drug delivery device 410 to an energy source, different drugs can be delivered at different times, in the proper sequence with respect to each other.

It should be appreciated that drug delivery device 410 may be one of the systems previously described herein. For example, drug delivery device 410 may have a lancet structure (fig. 1-4) or a barbed implant structure (fig. 5-7). The array shown in fig. 10 is formed from a lancet structure.

In another embodiment shown in fig. 11, any of the foregoing embodiments, including the array 400, may be connected to a biofeedback system 500 to control the delivery of the drugs in the array 400, the biofeedback system 500 including a microprocessor, programmable inputs, or the like. The biofeedback system 500 includes at least one sensor 510 in communication with the biofeedback system 500. During biofeedback, a special sensor 510 is placed on or within the body and may be incorporated into the lancet structure 130 or the support post 216. These sensors 510 measure clinically relevant materials used to detect, diagnose, monitor, or display regulation of bodily functions or their substitutes that cause problematic symptoms in the patient, such as heart rate, blood pressure, muscle tone (electromyographic or electromyographic feedback), brain waves (electroencephalographic or electroencephalographic feedback), respiration, and body temperature (thermal feedback), etc., and deliver information to the biofeedback system 500 where it is converted and displayed as a visual and/or audible reading. Optionally, the biofeedback sensor may be part of the transdermal drug delivery system 100, 200, 300, 400 described above, or may be one of the delivery systems described below.

The biofeedback system 500 is in communication with a controller 520, the controller 520 is coupled to each drug delivery device 410 of the array 400 and is configured to actuate (energize) each drug delivery device 410 at a particular point in time or to actuate only a portion of the drug delivery devices 410 using biofeedback information, rather than all as a function of the person's demand relative to a target value. As described above, this allows for controlled release of the drug to the patient, and since it is part of the biofeedback system, the information detected by the sensor 510 can be used to decide when and how to trigger drug release. For example, if the sensor 510 is measuring a property of the patient's blood and the measurement falls outside of an acceptable range, the sensor 510 will send a signal to the biofeedback system 500, which in turn signals the control system 520 to actuate one or more devices 410 containing a specific drug for administration to correct and counter the detected condition. Information from the biofeedback system 500 may also be sent to the control system 520 where it may be stored in the memory 531 and/or displayed 530 or transmitted for display to the patient and/or other persons, including physicians and/or managed care organizations, in a suitable manner to demonstrate the effect and/or progress of the treatment, either immediately or at a suitable time. The memory 531 may be an internal memory associated with the main controller 520 or it may be an external memory located remotely from the intradermal delivery device and accessed using a communication network as described below.

A communication subsystem 537 is provided for communicating information from the controller 520 to another device, such as an external device (e.g., a handheld device or computer coupled to the communication subsystem 537 via a network). Means for transmitting information (communication subsystem 537) include the use of a radio frequency transmitter or other suitable mechanical device.

The external device 539 (a ubiquitous device) is in communication with the subsystem 537, thereby allowing information and control signals to be communicated between the intradermal device (e.g., the subsystem 537) and the external device 539. The external device 539 thus comprises a receiver, which may be incorporated or may be a stand-alone device, such as a handheld device, e.g. a cell phone, a Personal Digital Assistant (PDA), a media player, e.g. an I-POD, or similar electronic device that itself contains an energy source, a Central Processing Unit (CPU) and interfacing software. In other words, the means for transmitting information is provided by a handheld device having a receiver, which may be provided by a component dedicated to performing the functions described herein or as part and feature of another device, such as a cell phone. Alternatively, the receiver 539 may be part of a common communications infrastructure service, such as WiFi, WiMax, cell tower, or the like. It should be understood that the interface should include signal transmission appropriate to the health maintenance organization, insurance company and/or managed care company, as well as the patient and physician, as already described. In this way, information can be easily transmitted from the intradermal delivery device to a person over a long distance by using an external communication device. The physician, etc., can thus monitor the measurements (biological properties) taken on the intradermal delivery device via the external device 539, and since the external device 539 is in communication with the intradermal delivery device, the physician can send control signals to the controller 520 to cause immediate release of the drugs, etc.

Again, it should be understood that the present device has both macro-sized and micro/nano-sized features, in particular, features that move into the intradermal space (e.g., microneedles, barbs, etc. as disclosed herein) are micro/nano, while the structures that support these (e.g., patches or housings as disclosed herein) are macro-sized because the structures are placed on the skin of the user.

To power the microcontroller 520 and any other electronic components that require power, an energy source or subsystem 541, such as a battery, is provided. A charger or other device for charging energy source 541 or otherwise powering energy subsystem 541 is provided for energy delivery 543.

It should also be appreciated that the array of drug delivery devices 410 may be part of a cartridge-based delivery system in which an applicator is used. The applicator comprises a compartment which movably accommodates the array cartridge and which suitably positions the drug delivery device 410 with respect to the electronic components of the applicator. The electronics, including the controller, communication subsystem, and energy subsystem, may be part of a fixed interface device that is adjacent to the compartment that houses the cartridge (e.g., by inserting an inner core through a slot). The user simply inserts the cartridge into the applicator which results in accurate alignment with the activation mechanism, thereby causing the implant to be selectively and controllably delivered to the patient, because the applicator's controller (microprocessor) can be programmed according to the patient's needs to sequentially activate a prescribed number of drug delivery devices 410 over a period of time to deliver the drug at set intervals and for that period of time. The patient may simply insert a new array cartridge daily/weekly/monthly, etc.

According to another embodiment, fig. 12 illustrates a transdermal delivery system 600. System 600 includes micro/nano movable barb assembly 610 and protective glue layer 620. In particular, assembly 610 includes a plurality of barbs 612 (which may be arranged in an array), barbs 612 extending from a resilient base 614 and having sharpened tips 616. The barbs 612 project from the base 614 and may be perpendicular thereto. The protective gel layer 620 is disposed opposite the base 614 because the protective gel layer 620 is located along the tips 616 of the barbs 612.

The barb configuration operates in the same manner as the barb configuration described above because the drug to be delivered is incorporated into the barb structure (implant). However, in this embodiment, the force of the implant comes from manually applying pressure to the top surface of the resilient base 614 or by using pressure applied by an applicator. The protective glue layer 620 provides: stable and environment-friendly micro/nano structures; a comfortable skin contact surface and the ability to incorporate a local anesthetic/antimicrobial to provide a benefit upon barb insertion.

When a force is applied to the top plane of the resilient base 614, the micro/nano-sized barb structures 612 penetrate the protective gel layer 620 and penetrate/enter the skin to a desired depth. The dimensions of the barbs 612 are therefore selected so that the barbs 612 are delivered to a desired location under the skin of a patient. Once the force applied to the base 614 is removed, the barbs 612 disengage from the support posts 216, staying in the desired position for dissolution/disintegration/resorption per application design for the prescribed treatment.

The resilient base 614 may be constructed from a variety of different materials and may have a variety of different configurations. For example, the resilient substrate 614 may be comprised of a pliable material that may be comprised of a plurality of functional layers, including a chemically "inert" barb protective layer, an anesthetic layer, and an adhesive layer, wherein the layers may be completely separate from one another or may be formulated in combination. The skin-contacting layer includes a local anesthetic from, but not limited to, (benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine (Alcaine), proxymetacaine, and tetracaine (also known as amethocaine) the anesthetic is incorporated into the adhesive layer, which is comprised of a cross-linked polymer or other material, preferably an inert substance such as silicon dioxide.

This type of system 600 may be used for pharmaceutical or cosmetic applications.

Fig. 13 illustrates an applicator 700 that may be used in conjunction with the system 600. The applicator 700 has a body 710 with an internal compartment 720, said internal compartment 720 comprising a first supply segment 722 and a second segment 724. The interior compartment 720 stores a supply of a drug delivery device containing a drug to be delivered. For example, a roll of micro/nano movable barb assemblies 610 and protective glue layer 620 can be disposed around a rotating shaft or gear 726, the rotating shaft or gear 726 allowing for the untwisting of the barb/glue assemblies. The body 710 may include one or more guide members 730 for arranging the order of the barb/glue assembly through the internal compartment 720 when the barb/glue assembly is unwound.

Along one surface 712 of the body 710, an applicator window 730 is formed for delivering the drug-containing structure (barbs/glue) to the patient. The roll of barbs/glue is arranged so that it passes adjacent the window 730 so that the glue layer 620 faces the window and the tips of the barbs face the window 730, allowing them to be implanted into the patient. To implant the barbs 612 in the patient, the applicator may be actuated to generate a force applied to the substrate 614, causing the barbs 612 to move forward from the windows 730, into the patient's skin as described above.

After implanting a predetermined number of barbs 612 (such as those visible from the window 730), the applicator 700 is manipulated to move the roll forward and the passing micro/nano barbs 612 are rolled up by a spindle or gear 740. For example, the applicator 700 may include a knob that, when rotated, may cause forward movement of the barb feed. Other devices may be used as well. The order of the barbs 612 and the layer of gel 620 is arranged in the body 710 so as to be presented to the window 730 in a manner that causes the barbs 612 and the layer of gel 620 to protrude beyond the surface 712, so that the barbs 612 are implanted when the applicator 700 is pressed against the skin so that the surface 712 is placed in contact with the skin. Alternatively, the applicator may have some type of activation device that applies a force to the substrate 614 to cause the barbs 612 to be implanted.

It should also be appreciated that the roll of micro/nano movable barb assembly 610 and protective gel layer 620 may be part of a cartridge and, thus, applicator 700 may be a cartridge-based system. The electronics of the applicator 700, including the controller, etc., are located on a more fixed interface device. The patient simply inserts a new array cartridge daily/weekly/monthly, etc.

Examples

One application of drug delivery systems is the human ear. More specifically, the barbed implant designs of fig. 5-7 may be configured as anti-infective implant formulations for prophylactic administration or as therapeutic agents in middle ear infections. The barbed implant is attached to a topical application (e.g., similar to a swab (Qtip) or film) and the barb-based formulation is applied to the outer surface of the tympanic membrane to allow the micro/nano barbs to penetrate the membrane and enter the area of the middle ear where the barbs with the anti-infective agent (antibiotic) are placed for the prevention or treatment of the existing infected ear cavity. The applicator may take the form of a glue, spray or multilayer film, which may include a local anesthetic to facilitate application to the area to which the nerve has been sensitized.

Examples

Another example is that the barbed implant design of Figs. 5-7 may be configured as an anti-infective or anti-allergic implant formulation for prophylactic administration or as a therapeutic agent in nasal infections or rhinitis. The barbed implant is attached to a topical application (e.g., similar to a swab (Qtip) or film, or spray) and the barb-based formulation is applied to the nasal mucosa to allow the micro/nano barbs to penetrate the membrane and enter the area of the middle ear where the barbs with anti-infective agents (antibiotics), anti-allergic agents (antihistamines, etc.) are placed for the prevention or treatment of existing infected nasal cavities. The applicator may take the form of a glue, spray or multilayer film, which may include a local anesthetic to facilitate application to the area to which the nerve has been sensitized.

Examples

Another application is for tumor/organ encapsulation (wrap) which is set up for direct infusion of sustained release agents. The wrap is made of "fabric" or crimped polymer skin to actuate "barbs" (barb) to open the access and allow the delivery of the agent activity to the target tissue. The wrap may be applied laparoscopically (laproscopically) by spraying or rolling.

In another embodiment, the transdermal delivery system disclosed above may be part of a system that provides a visual indicator of whether the application of a drug to a person using the system was successful. For example, the applicator and the barb may be constructed such that when the barb is released (implanted) into the skin of the patient, a color change occurs, thus providing a visual indicator or confirmation of a successful delivery result. In other words, when the barb is removed from the support post or other support structure, a color change results. This can occur by having the support post distal end composed of: the material changes color when the surrounding barbed implant is detached and exposed to air. Alternatively, the ends of the support posts may have a color that is initially covered by the barbed implant, but that is exposed when the barbed implant is implanted in the patient.

The user of the system can thus easily determine how many barbed implants were successfully delivered to the patient. For example, when the barbed implant is positioned on the end of a swab, after the swab is pressed against the patient's skin, it can be easily shown, simply by observing the surface of the swab, what area of the swab successfully delivered the barbed implant. The user will see an area of colorless (or first color) indicating whether the implant is intact and an area of another color indicating successful implantation.

Another delivery system application includes the system described above, wherein the substance is delivered locally and below the stratum corneum, and has a composition that swells after implantation, such that pressure can be applied to the stratum corneum from below the surface. One application of such topical applications is to reduce the appearance of wrinkles or to tighten the skin surface.

For example, the barbed implants disclosed herein may be part of a cosmetic wrinkle reduction system. The system can help anyone who wishes to reduce or temporarily eliminate facial wrinkles (around the mouth, nose, eyes, etc.) commonly associated with aging by easily and painlessly implanting an appropriate amount of an expanding barbed implant between the stratum corneum and the germinal layer where interstitial fluid causes the barbs to spread and apply appropriate pressure to the stratum corneum to fill the furrows that cause the wrinkles. The barbed implant may be constructed from materials that are endogenous to the body and materials that can be compounded to form an expanded hydrogel-type matrix. As with the other embodiments, the barbed implant will be absorbed and eliminated without potential accumulation.

Referring now to fig. 14-22, additional embodiments are illustrated. In fig. 14, a device 800 as part of a micro/nano transdermal delivery system includes at least one, and preferably a plurality of microneedles 810, with channels 820 formed in the microneedles 810. The microneedles are mounted on an oscillating movable base 830. The device 800 includes a stationary housing 802, the housing 802 being open along a base 804 thereof. In the illustrated embodiment, the stationary housing 802 has a top portion 804 that encloses the stationary housing 802. The movable base 830 is located adjacent the top portion 804 and extends across the side wall 805 of the housing 802.

Contact between the surface of the device (e.g., substrate surface 807) and the skin is controlled and limited by the stationary housing 802. The microneedles 810 oscillate at a frequency of between about 0kHz and about 3MHz (preferably between about 5kHz and about 2MHz) and an amplitude of between about 0 and about 1000 microns (preferably between about 5 microns and about 250 microns) as a result of the activation of the base 830. The amplitude of the oscillation is different for the drilled/open channels in the stratum corneum/epidermis/dermis and/or the pumping/suction of drugs/blood/interstitial fluid. Oscillating the microneedles 810 (relative to the fixture housing 802) creates holes in the stratum corneum with defined characteristics. The design of the microneedles 810 varies according to specific requirements and depends on the particular application. The generation of back pressure and/or stratum corneum-device 800 interface pressure drives the drug to the target level in the intradermal space.

Fig. 14 shows a basic device 800 for delivery of a drug and extraction of a fluid, such as blood and/or interstitial fluid. Figure 14 shows the device 800 in a normal resting position in which the microneedles 810 do not extend to an out-of-plane delivery or extraction position. Figure 15 shows the device 800 in an activated state, in which the base 830 has oscillated relative to it in the position of figure 14, which causes the microneedles 810 to move out of plane, such that the distal tips 812 of the microneedles 810 extend below the basal surface 807 of the device 800 (housing 802). Fig. 14 and 15 show 2 channels 820 formed therein. The channels 820 may have the same configuration or, as shown, contain different configurations. Fig. 15 thus shows out-of-plane oscillation with the distal tip 812 advanced into the skin to the desired depth as described herein.

In fig. 15, each channel 820 includes a fluidic device 850, 852 (e.g., a directional valve/pump) included in the respective channel 820 to control the flow in the channel 820 that needs to be controlled. The fluidic elements 850, 852 are in communication with the main controller/processor of the device 800 to allow control thereof depending on the precise application and state of the microneedles 810. Additional fluidic devices may be provided in the device, located away from the actual channel to control the flow of fluid within the device.

Figure 16 shows a device 900 which includes many different types of microneedle configurations, particularly channel configurations. It should be understood that the illustrated device 900 may include one type of microneedle configuration or a combination of different types of microneedle configurations. For example, figure 16A shows a microneedle 810 having a passive free-flow channel configuration. In particular, the microneedles 810 include individual channels 820, the channels 820 having a primary section 822 that opens at the top and bottom of the microneedles 810, and a side or secondary section 824 that includes an opening along the side of the microneedles 810, before the distal tip 812. The liquid flows freely in both directions within the channel. Figure 16B shows a microneedle 810 of a different configuration in which there is a single channel 820 with flow control. In particular, the single channel 820 is similar to the channel shown in fig. 16A in that the channel 820 has a primary section 822 that opens at the top and bottom of the microneedles 810 and includes a side or secondary section 824 that has an opening along the sides of the microneedles 810 before the distal tip 812. At or near the top end of the primary segment 822, a directional valve/pump 850 is included for controlling the flow to be controlled in the channel 820. The fluidic element 850 communicates with the main controller/processor of the device 800 to allow control thereof depending on the precise application and state of the microneedles 810.

Figure 16C shows a microneedle 810 similar to that of figures 16A and 16B; however, in this embodiment, the microneedles 810 have a multi-channel configuration. More specifically, microneedle 810 includes a first channel 820 and a second channel 821. First passage 820 opens at the top end and opens at the distal end. The second channel 821 opens at the top and along the sides of the microneedle 810. At or near the top of first segment 820 and second passage 821, directional valves/pumps 850, 852 are included in the respective passages to control the flow to be controlled in passages 820, 821. The fluidic element 850 communicates with the main controller/processor of the device 800 to allow control thereof depending on the precise application and state of the microneedles 810.

Figure 16D shows a microneedle 810 comprising a backpressure channel. More specifically, the microneedle 810 includes a primary channel 815 having a top end and a bottom end, the bottom end opening at the distal tip of the microneedle 810. A side or back channel 831 is provided in the microneedle 810 such that one end of the side channel 831 opens along the side of the microneedle 810 and the other end communicates with the main channel 815. At a location above the connection point between the side passage 831 and the main passage 815, a directional valve/pump 850 is included in the respective passage to control the flow to be controlled in the passage. The fluidic element 850 communicates with the main controller/processor of the device 800 to allow control thereof depending on the precise application and state of the microneedles 810. The arrows shown in fig. 16D reflect the liquid flow.

Figure 17 shows the back pressure microneedle embodiment of figure 16D installed in a device for use in a micro/nano transdermal delivery system. In fig. 18, there are 2 fluidic elements 850 that allow fluid to be controlled as it flows in the device, for example when a drug to be delivered flows into the microneedles 810. In fig. 17, the microneedles 810 are in a normal resting position in which the distal ends of the microneedles 810 do not extend beyond the bottom of the device (housing). Figure 18 shows the microneedles 810 in an actuated state (oscillating out of plane) in which the microneedles 810 extend out of the housing, causing the distal tips of the microneedles 810 to be driven into the skin.

Fig. 19 shows a subunit 1000 constructed in accordance with the present invention. The unit 1000 includes a body 1010 having a reservoir 1020 containing a drug, the reservoir 1020 being contained between a pair of substrates or layers 1022. Layer 1022 may be in the form of an actuator configured to selectively activate one or more microneedles 810. For example, layer 1022 may be comprised of a piezoelectric sheet that changes shape when energized by a small amount of current, as is well known. Layer 1022 may be another type of actuator, such as a pressure actuator and/or a motion actuator, which, under selected conditions, causes deformation of unit 1000 in a manner described below, resulting in the controlled release of the drug contained in reservoir 1020.

The unit 1000 includes at least one, and preferably a plurality of microneedles 810 in selective communication with a reservoir 1020. The precise structure and interface between the reservoir 1020 and microneedles 810 may vary depending on the particular application and other considerations. For example, there may be a main channel 1030 in selective communication with the reservoir, as a valve/pump 1040 is provided in or at the end of the main channel 1030 to control the flow of medicament from the reservoir 1020. The main channel 1030 also communicates with an external channel network that delivers fluid from the reservoir to a number of channels that feed the microneedles 810 directly and allow drug to flow out through the distal tips of the microneedles 810.

The unit 1000 also includes a biofeedback system 500 in communication with a controller 520, the controller 520 being connected to each drug delivery device (in this case, microneedles 810) of the array and being set to actuate (energize) each microneedle 810 at a particular point in time, or to actuate only a portion of the microneedles 810 using biofeedback information, not all as a function of the person's needs relative to the target value. As described above, this allows for a controlled release of the drug to the patient, and since it is part of the biofeedback system, the information detected by the sensor 510 can be used to decide when and how to trigger the drug release. For example, if the sensor 510 is measuring a property of the patient's blood and the measurement falls outside of an acceptable range, the sensor 510 will send a signal to the biofeedback system 500, and the biofeedback system 500 in turn signals the control system 520 to actuate one or more microneedles 810 containing a specific drug for administration to correct and counter the detected condition

Information from the biofeedback system 500 may also be sent to a control system where it may be stored and/or displayed 530 or transmitted for display to the patient and/or other persons, including physicians, at an instant or at an appropriate time and in an appropriate manner to demonstrate the effect and/or progress of the treatment. The means for transmitting information includes the use of a radio frequency transmitter or other suitable mechanical device, such as a communication subsystem 505 shown generally in fig. 19. As referred to above, the receiver may be incorporated or may be a stand-alone device, such as a handheld device, e.g. a cell phone, a Personal Digital Assistant (PDA), a media player (e.g. an I-POD) or similar electronic device that itself comprises the energy source, a CPU and interface software. In other words, the means for transmitting information is provided within a handheld device having a receiver, and it may be provided by a device dedicated to performing the functions described herein or may be provided as part of another device, such as a cell phone, and features. Alternatively, the receiver may be part of a common communications infrastructure service, such as WiFi, WiMax, cell tower, etc. It should be understood that the interface should include signal transmission appropriate to the health maintenance organization, insurance company and/or managed care company, as well as the patient and physician, as already described.

It should also be appreciated that the biofeedback system 500 disclosed herein is not limited to use as part of or in combination with a larger drug delivery device. Instead, all of the drug delivery devices disclosed herein may be modified so as to not include a drug delivery element (e.g., a reservoir) or if such an element is present, communication from the feedback system 400 to the control system is for diagnostic purposes only and is not associated with signals or instructions related to drug release. In other words, the biofeedback system may communicate with a control system that may store and/or display the received information regardless of drug delivery.

Referring now to FIG. 20, another subunit 1100 is shown. The subunit 1100 includes a stationary housing 802, the stationary housing 802 enclosing the drug-containing reservoir 110, microneedles 810, and other components. In the illustrated embodiment, the reservoir 110 is in communication with at least one actuator. For example, one or more pressure actuators 1110 may be provided for applying a selected force to a localized area of the cell. In the illustrated embodiment, the pressure actuator 1110 is located along the top of the reservoir 110. Additionally, one or more motion actuators 1120 may be provided, and in the illustrated embodiment, a plurality of motion actuators 1120 are located along the bottom of the reservoir 110 and spaced apart from one another. The motion actuator 1120 is positioned so as not to block the flow of drug in the microneedle 810 from the reservoir 110 to the top of the main channel 821. The combination of these actuators provides a means of actuating selected microneedles 810 to move ("fire") the microneedles 810 forward into the patient's skin and allow the microneedles to return to their normally withdrawn, resting position.

For other embodiments, one or more valves/pumps 1130 may be provided for controlling the flow of fluid within the device. For example, one valve/pump 1130 may be provided in the communication link between the reservoir 110 and the sensor 510, and one or more valves/pumps 1130 may be provided between the reservoir 110 and the channel structure. With other embodiments, the microneedles 810 may extend out of the housing and into the skin.

Fig. 21 shows another sub-apparatus 1200. This embodiment is similar to the other embodiments; however, in this embodiment, there are piezo patches 1210 located along the top and bottom of the reservoir 110. Thus, the sheet 1210 defines the interior of the reservoir 110. Actuation of the piezoelectric sheet 1210 causes selective excitation (deformation) of certain microneedles 810.

Fig. 22 discloses an alternative micro/nano drug delivery device 1300, which depicts a biosensor interface and drug delivery subunit and control system. The device 1300 includes the subunit 1200 shown in fig. 21, and further includes a biofeedback system 500 in communication with the controller 520, the controller 520 being connected to each drug delivery device (in this case, microneedles 810) of the array and being set to actuate (energize) each microneedle 810 at a particular point in time, or to actuate only a portion, but not all, of the microneedles 810 as a function of human demand relative to a target value using biofeedback information. And (4) actuating. As described above, this allows for controlled release of the drug to the patient, and since it is part of the biofeedback system, the information detected by the sensor 510 can be used to decide when and how to trigger drug release. For example, if the sensor 510 is measuring a property of the patient's blood and the measurement falls outside of an acceptable range, the sensor 510 will send a signal to the biofeedback system 500, and the biofeedback system 500 in turn signals the control system 520 to actuate one or more microneedles 810 containing a specific drug for administration to correct and counter the detected condition.

In the illustrated embodiment, the sensor 510 is disposed proximate (adjacent) to the reservoir 511, the reservoir 511 being in selective communication with the reservoir 110 via the conduit or channel 111. A pump/valve 850 is disposed along the conduit 111 to allow flow between the reservoirs 511, 110. Other pump/valves 850 are disposed in communication with the microneedle channels to selectively allow fluid flow between the reservoir 110 and the microneedles 810. A pressure actuator 1310 is provided which is located in the reservoir 511 adjacent the sensor 510.

As shown in fig. 22, the electronic controller 520 is in communication with the working components of the device, including the pump/valve 850, the sensor 510, the pressure actuator 1310, etc.

Information from the biofeedback system 500 may also be sent to a control system where it may be stored and/or displayed or transmitted for display to the patient and/or other persons, including physicians, at an instant or at an appropriate time and in an appropriate manner to demonstrate the effect and/or progress of the treatment. The means for transmitting information may include the use of a radio frequency transmitter or other suitable mechanical device. As referred to above, the receiver may be incorporated or may be a stand-alone device, such as a handheld device.

The apparatus of fig. 14-22 is configured to perform a number of different operations. For example, in one embodiment, a negative back pressure (difference) is used to draw blood and/or interstitial fluid from the intradermal region into an appropriate reservoir (e.g., 511 in FIG. 22) and into contact with sensor 510. Pressure oscillations and motion control (e.g., using the disclosed actuators, piezoelectric patches, etc.) are used to move fluid into and out of the reservoir 511 into and out of contact with the sensor 510. The pressurized reservoir uses a synchronization scheme. The frequency and duty cycle and synchronization are optimized for maximum performance. Biological samples can be obtained using a variety of different techniques as described above.

Biosensing of biological materials can be achieved by using electrical/electrochemical/mass (mass) detection. The system may utilize one or more of the following: i) applying a dc voltage and measuring a dc current response (amperometry), ii) applying a dc current and measuring a dc voltage response (potentiometry), or iii) applying an ac voltage and measuring an ac current response (capacitance or impedance). In all cases, three electrodes: the working, reference and counter electrodes are incorporated into an intradermal delivery, diagnostic and communication device. The electrodes are placed as close together as possible and analyte detection occurs at the working electrode. Ideally, the electrodes are designed so that a voltage is applied between the working and reference electrodes and a current is detected through the counter electrode. The mass deposition of the functionalized surface can be detected by inertia based methods, such as a shift in the resonant frequency of the cantilever due to a change in mass.

Examples

The following is a general description of how the device of fig. 14-22 may be used for drug delivery applications. In the first step, the backpressure is raised or oscillated out of phase with the microneedle motion. This results in the stratum corneum being pecked out in the duty cycle (defined in terms of frequency, amplitude or duration) and creating multiple holes in the stratum corneum. Large drug molecules are forced through the stratum corneum due to (oscillatory) back pressure movements. In a subsequent step, the "pecking movements" are stopped, maintaining a (static) back pressure until the pores of the stratum corneum close/heal.

According to one embodiment, operating the diagnostic mode includes, reducing back pressure (or oscillating back pressure out of phase with needle movement); pecking out the stratum corneum (frequency, amplitude and duration) during the duty cycle; thereby creating a plurality of pores in the stratum corneum. This forces blood/interstitial fluid from these pores through the stratum corneum into the drug-containing sensor reservoir due to the (oscillating) negative back pressure.

The pecking motion is stopped and the backpressure is raised to the internal body pressure until the stratum corneum pores close/heal. The apparatus and methods of the present invention may achieve many advantages, including but not limited to the following: the time required to contact the top of the stratum corneum is very short (microseconds because of the short operating timescale (kHz-MHz)); no long-term contact with the top of the stratum corneum is required, since the device can be activated when contact is established; only a short time (i.e., microseconds) in contact with the stratum corneum; macromolecules can be delivered through "macropores" in the stratum corneum (due to microneedle size); multiple drug delivery is possible due to the modular design and fast operation of the reservoir/sensor; time to stratum corneum healing due to microsecond operation and hours of use (rest); minimally invasive; rapid blood/fluid extraction enables multiple tests/monitoring; a large number of control parameters (amplitude, frequency, duration, etc.) provide flexibility in the design, operation, and use of the device; due to the short operating time, very fast real-time dose modification (if required) is possible; may be programmed for continuous, patterned, on-demand, or feedback controlled drug delivery/monitoring; new microneedle designs can be integrated, which provides greater flexibility in delivery design and utilization schemes; active process control is possible due to the large number of control parameters; short operation times minimize energy consumption; the modular design allows for the dispersion of chemical permeation enhancers and the integration of thermal/ultrasonic/electrical enhancement elements.

It should be understood that the elements shown in fig. 14-22, including the sensor and drug delivery device, are suitable for use in the system generally illustrated in fig. 11.

Although the invention has been described in connection with certain embodiments, the invention can be embodied in other forms and using other materials and structures. Accordingly, the invention is defined by the recitations in the claims appended hereto and their equivalents.

Claims (18)

1. An intradermal delivery system, comprising:

at least one micro/nano-sized drug delivery device for delivering a drug intradermally beneath the stratum corneum, the drug being stored in a reservoir within the device, the device having an actuator that causes selective movement of at least a portion of the device to deliver the drug beneath the stratum corneum, wherein the drug delivery device comprises:

a stationary housing having top and side walls defining a hollow interior, the housing having a fully open bottom between the side walls such that a bottom edge of the side walls is available for placement against the skin of a patient, and

a movable base disposed within the hollow interior of the housing such that the movable base extends between the side walls of the housing, the base being movable relative to the stationary housing, wherein the movable base has at least one microneedle integrated therewith and extending outwardly from a bottom surface of the base such that the microneedle can move as part of the movable base a sufficient distance to cause the microneedle to contact and penetrate the stratum corneum;

a programmable controller in communication with at least one of the devices for controlling actuation of the actuator;

a biofeedback device in communication with the programmable controller and including at least one biosensor that measures at least one biological property of the patient,

wherein the controller is programmed based on the patient's needs to deliver the drug at a prescribed time or based on signals received from the biofeedback device;

a first channel formed in said base at a location remote from and spaced apart from said microneedle, wherein said microneedle has a main channel opening at the tip of said microneedle and a side channel opening along the side of said microneedle and communicating with said main channel; and

a plurality of fluidic elements located within the first channel and within the main channel above a connection point between the main channel and the side channel;

wherein the actuator is operably connected to the movable base to cause controllable movement of the base to cause movement of the microneedles such that in the extended position the drug delivery tips of the microneedles are advanced beyond the bottom edge of the stationary housing and into the skin beneath the stratum corneum, wherein in the retracted position the drug delivery tips are located within the interior of the stationary housing above the bottom edges of the sidewalls to be spaced from the skin when the bottom edges of the stationary housing are resting on the skin.

2. The system of claim 1, wherein said actuator causes said movable base to oscillate, causing said microneedles to oscillate at a frequency greater than 0kHz and not greater than 3MHz with an amplitude greater than 0 microns and not greater than 250 microns.

3. The system of claim 1, wherein a primary channel in the microneedle is in selective communication with the reservoir to allow the drug to flow through the primary channel to the open distal tip.

4. The system of claim 1, wherein the flow control element comprises a directional valve or a directional pump.

5. The system of claim 1, wherein there are a plurality of microneedles, each microneedle being actuatable and displaceable independently of the other needles.

6. The system of claim 1, wherein the actuator comprises first and second piezoelectric patches arranged such that the reservoir is located therebetween, the first and second piezoelectric patches being operably connected to an energy source.

7. The system of claim 1, wherein the actuator is at least one actuator selected from a pressure actuator and a motion actuator.

8. The system of claim 1, wherein the biosensor is in selective communication with the reservoir via a channel having fluidic means disposed along the channel for restricting flow between the biosensor and the reservoir.

9. The system of claim 1, wherein the biosensor is integrated with a body of the at least one drug delivery device.

10. The system of claim 1, wherein the biofeedback device is in wireless communication with a programmable controller.

11. The system of claim 1, wherein the biofeedback device measures a biological property and sends a signal containing information about the measured biological property to the programmable controller.

12. The system of claim 11, wherein the programmable controller is in communication with an external device, the external device including at least one of a display and a memory capable of storing information, the display capable of displaying information about the measured biological property.

13. The system of claim 12, wherein the external device is a handheld device and the communication comprises wireless communication between the handheld device and the controller.

14. The system of claim 1, wherein said actuator creates a back pressure in said microneedle causing fluid to flow into said microneedle, into said reservoir, and into contact with a biosensor.

15. The system of claim 14, wherein the fluid is one of blood and interstitial fluid.

16. The system of claim 1, further comprising a second channel between the biosensor and the reservoir, the second channel having a fluidic element therein for controlling the flow of liquid, wherein the second channel is located along a top of the reservoir and the microneedles are located along a bottom of the reservoir.

17. The system of claim 1, wherein the actuators comprise one or more pressure actuators and a plurality of motion actuators, wherein the pressure actuators are located at a top of the reservoir and the motion actuators are located along a bottom of the reservoir and spaced apart from each other.

18. The system of claim 17, wherein the motion actuator is located between a plurality of microneedles.