Abstract:
Products and methods directed to the improved infusion of fluids are disclosed. Such products and methods can be used to more efficiently and efficaciously administer therapeutic pharmaceuticals to a subject in need of treatment. In many instances, the systems comprise a therapeutic fluid delivery system and a mechanism for enhancing the absorption of the therapeutic fluid. The enhancement of the absorption of the therapeutic fluid is generally performed locally i.e., at or near the site of administration of the therapeutic fluid. The system and methods can be used to deliver any number of therapeutic fluids including but not limited to insulin.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is the U.S. national stage entry under 35 USC §371 of International Application No. PCT/IL2009/000827, filed Aug. 27, 2009, which claims priority to U.S. provisional application Ser. No. 1/092,412entitled “Device and Method for Enhanced Subcutaneous Insulin Absorption”, filed Aug. 28, 2008, the content of which is hereby incorporated by reference in its entirety. 
    
    
     FIELD 
     The present invention relates generally to a method and a device for sustained infusion of fluids. More particularly, the invention relates to a skin securable device that delivers fluid to the subcutaneous tissue and a method for enhancement of fluid absorption into the systemic circulation. 
     BACKGROUND 
     Diabetes Mellitus and Insulin Pumps 
     Diabetes mellitus is a disease of major global importance, increasing in frequency at almost epidemic rates, such that the worldwide prevalence in 2006 is 170 million people and predicted to at least double over the next 10-15 years. Diabetes is characterized by a chronically raised blood glucose concentration (hyperglycemia), due to a relative or absolute lack of the pancreatic hormone, insulin. 
     Treatment of diabetes mellitus requires frequent insulin administration that can be done by multiple daily injections (MDI) with syringe or by continuous subcutaneous insulin injection (CSII) with insulin pumps. In recent years, ambulatory portable insulin infusion pumps have emerged as a superior alternative to multiple daily injections of insulin. These pumps, which deliver insulin to the subcutaneous tissue at a continuous basal rate as well as in bolus volumes, were developed to liberate patients from repeated self-administered injections, and allow greater flexibility in dose administration. 
     Several ambulatory insulin infusion devices are currently available on the market. Examples of first generation disposable syringe-type reservoir and tubes were disclosed in U.S. Pat. No. 3,631,847 to Hobbs, U.S. Pat. No. 3,771,694 to Kaminski, U.S. Pat. No. 4,657,486 to Stempfle, and U.S. Pat. No. 4,544,369 to Skakoon. Other dispensing mechanisms have also been disclosed, including peristaltic positive displacement pumps, in U.S. Pat. No. 4,498,843 to Schneider and U.S. Pat. No. 4,715,786 to Wolff. 
     Although these devices represent an improvement over multiple daily injections, they nevertheless all suffer from several drawbacks. The main drawback is the large size and weight of the device, caused by the configuration and the relatively large size of the driving mechanism and of the syringe. This relatively bulky device has to be carried in a patient&#39;s pocket or attached to the belt. Consequently, the fluid delivery tube of the infusion set is very long, usually longer than 60 cm, in order to permit needle insertion at remote sites of the body. These uncomfortable bulky devices and long infusion set are rejected by the majority of diabetic insulin users, since they disturb regular activities, such as sleeping and swimming. In addition, the delivery tube excludes some optional remote insertion sites, like buttocks, arms and legs. 
     To avoid the consequences of a long infusion set, a new concept, a second generation pump, has been proposed. This concept includes a remote controlled skin adherable device with a housing having a bottom surface adapted to contact patient&#39;s skin, a reservoir disposed within the housing, and an injection needle adapted to communicate with the reservoir. These skin adherable devices are disposed every 2-3 days similarly to available pump infusion sets. These devices were disclosed at least in U.S. Pat. No. 5,957,895 to Sage, U.S. Pat. No. 6,589,229 to Connelly, and U.S. Pat. No. 6,740,059 to Flaherty. Additional configurations of skin adherable pumps were disclosed in U.S. Pat. No. 6,723,072 to Flaherty and U.S. Pat. No. 6,485,461 to Mason. These devices also have several limitations: they are also bulky and expensive. Their high selling price is due to the high production and accessory costs; the user must discard the entire device every 2-3 days, including the relatively expensive components, such as the driving mechanism and electronics. 
     A third generation dispensing device, described in co-pending/co-owned U.S. patent application Ser. No. 11/397,115, and International Patent Application Nos. PCT/IL06/001276 and PCT/IL09/000,388, whose disclosures are hereby incorporated by reference in their entireties, has been recently developed. This third-generation device is a miniature portable programmable fluid dispenser that has no tubing and can be attached to the patient skin. It is composed of two parts, a disposable part (DP) and a reusable part (RP). After connection of the reusable and the disposable parts, the unified dispensing unit presents a thin profile. The RP contains electronics and other relatively expensive components and the DP contains reservoir. This device comprises a remote control unit that allows data acquisition, programming, and user inputs. An improvement to the skin adherable pump disclosed above is described in co-pending/co-owned U.S. patent application Ser. No. 12/004,837 and International Patent Application No. PCT/IL07/001,578, the disclosures of which are also incorporated herein by reference in their entireties. In this application, an improved system and a method for connection and disconnection of a skin securable pump is disclosed. The method uses a cradle, which is initially adhered to the skin and then a cannula is inserted through the cradle into the body of the user. The two-part pump can be consequently connected and disconnected to and from the cradle upon patient&#39;s discretion. 
     Partly in response to the need for tighter glycemic control, closed loop infusion systems, as the system described in U.S. Pat. No. 6,558,351 assigned to Medtronic MiniMed, have been developed. This system comprises a sensor system (e.g. a continuous glucose monitor, CGM), and a delivery system (i.e., insulin pump). The systems are interconnected via a controller a separate components, both comprising separate tubing and separate cannulae that are applied to the body of the user. A new generation of a dual function device and/or system is described in U.S. patent application Ser. Nos. 11/706,606 and 11/963,481, and in International Patent Application No. PCT/IL08/001,521, whose disclosure is also incorporated by reference in its entirety, assigned to Medingo Ltd. The device is a single skin securable patch employing a single subcutaneous cannula. 
     One of the main hurdles in perfecting a semi-invasive closed loop system (i.e., sensor and delivery systems located in the subcutaneous tissue) stems from the lag time between insulin delivery and peak glucose lowering effect. This lag time can be shortened with development of more rapid insulin analogues and/or with better insulin absorption from the subcutaneous tissue. 
     Insulin Absorption 
     When a bolus of rapid acting insulin, commonly used in insulin pumps, is administered to the subcutaneous tissue before a meal, insulin effect usually lags behind glucose absorption and consequently blood glucose rises and peaks, as can be seen in  FIG. 1 . This figure shows curves of blood glucose and insulin levels (y axis) over time (x axis) after a meal intake and an insulin bolus, and the lag period between glucose and insulin blood levels peaks. Blood insulin levels usually lag behind blood glucose levels when insulin is administered at the time of oral glucose intake. This phenomenon consequently leads to blood glucose rises and peaks, as can be seen in the figure. An enhanced absorption of insulin will shorten the lag period between glucose and insulin blood levels&#39; peaks and thus mitigate the described postprandial hyperglycemia. 
     Changes in blood glucose concentrations are proportional to rate of insulin absorption from the injection site into the systemic circulation. This absorption rate is determined by several factors, including the circulation of blood in the vicinity of the injection site, and the permeability of the walls of the relevant blood vessels. Insulin absorption at the injection site is enhanced with increased blood flow and/or blood vessel wall permeability at the subcutaneous tissue and reduced with decreased blood flow and/or blood vessel wall permeability. Increased subcutaneous blood flow and/or blood vessel wall permeability may be promoted by vasodilatation of the subcutaneously located blood vessels. Such vasodilatation may be achieved by different methods, including the following:
     Local heat; It has been shown that, for example, the disappearance rate of insulin from subcutaneous tissue in the sauna was two-fold greater than in room temperature (Br Med J. 1980 Jun. 14; 280(6229): 1411-1413). U.S. Pat. No. 6,756,053 assigned to Zars Inc., describes a method for enhanced transdermal drug delivery by controlled heating. One method for providing controlled heating is ultra sound; Ultra Sound is commonly used to generate deep heat in physical therapy and as an adjunct to wound healing by promoting blood flow to the injured tissue. Another method for achieving local heating is high frequency vibration.   Current application; Monopolar current applications are often used to increase the migration of vasoactive drugs through the skin, a technique known as iontophoresis. It has been reported that in parallel to the ‘specific’ vasomotor physiological effect resulting from the diffused drug, a ‘non-specific’ vasodilatation occurs as a result of the current application itself. The amplitude of this current-induced vasodilatation depends on the electrical charge (Journal of Physiology 2002, 540(1), 261-269). The ‘non-specific’ vasodilatory effect can be applied intentionally to achieve enhanced subcutaneous blood flow.   UV light; Increased blood flow after low dose irradiation of the human skin with UV at 250 and 300 mu has been demonstrated (British Journal of Dermatology 1976 94 (5) 487-493).   Pharmacologic agents; Agents such as nitroglycerin, nitroprusside, histamine, PDE5 inhibitors (e.g., sildenafil), and papaverine are vasodilating agents known in the art.   

     In order to achieve an accelerated insulin absorption rate and thus a more rapid glucose lowering effect, it is desirable to provide an insulin pump and a method for accelerating insulin absorption by promoting a vasodilatory effect on the subcutaneous blood vessels. 
     It is also desirable to provide a device that delivers insulin into the body and can concomitantly monitor body glucose (e.g., blood, ISF) levels and a method for promoting a vasodilatory effect on the subcutaneously located blood vessels. More specifically, it is advantageous to provide an improved semi-invasive closed loop drug delivery system (i.e., sensor and delivery systems located in the subcutaneous tissue) wherein the lag time between delivery of the drug (e.g., insulin) and peak pharmaceutical effect (e.g., glucose lowering), which comprises a mechanism for increasing drug absorption from the subcutaneous tissue. 
     It is also desirable to provide a device which is miniature, discreet, economical for the users and highly cost effective and a method for promoting a vasodilatory effect on the subcutaneous blood vessels. 
     It is also desirable to provide a device that contains a miniature skin securable dispensing patch unit that can continuously dispense insulin and a method for promoting a vasodilatory effect on the subcutaneous blood vessels. 
     It is also desirable to provide a device that comprises an insulin dispensing patch unit that can be remotely controlled and a method for promoting a vasodilatory effect on the subcutaneous blood vessels. 
     It is also desirable to provide a device that contains a miniature skin securable patch that can continuously dispense insulin and monitor body glucose concentration levels and a method for promoting a vasodilatory effect on the subcutaneous blood vessels. 
     It is also desirable to provide a miniature skin securable patch that can continuously dispense insulin and continuously monitor body glucose concentration levels and a method for promoting a vasodilatory effect on the subcutaneous blood vessels. 
     It is also desirable to provide a device that includes a closed or semi-closed loop system that is capable of monitoring glucose levels and dispensing insulin according to the sensed glucose levels and a method for promoting a vasodilatory effect on the subcutaneous blood vessels. 
     SUMMARY 
     The present invention discloses a portable device that delivers therapeutic fluid into the body (i.e., insulin) and a method for enhancing therapeutic fluid absorption from the injection site into the systemic circulation. 
     The dispensing device according to the invention comprises a dispensing patch unit and in some preferred embodiments a remote control unit which communicates with the dispensing patch unit and allows programming of therapeutic fluid delivery, user input and data acquisition. The dispensing patch unit can be connected to a subcutaneously cannula through which insulin is delivered to the body. In some preferred embodiment, the patch unit is composed of two parts—a disposable part (DP) and a reusable part (RP). In one preferred embodiment a cradle unit is provided which is a flat sheet that adheres to the skin and allows patch disconnection and reconnection upon patient discretion. After attachment of the cradle unit to the skin, a cannula is inserted into the subcutaneous compartment through a dedicated passageway in the cradle unit. 
     In one aspect, the invention contemplates an improved semi-invasive closed loop drug delivery system (i.e. sensor and delivery systems located in the subcutaneous tissue) wherein the lag time between delivery of the drug (e.g. insulin) and peak pharmaceutical effect (e.g., glucose lowering), which comprises a mechanism for increasing drug absorption from the subcutaneous tissue. In one embodiment the increase in drug absorption is accomplished through, vasodilatation. In a preferred embodiment the vasodilatation is accomplished through heating of the tissue at the site of drug delivery. In a most preferred embodiment both the heating and drug delivery are subcutaneous. 
     In one preferred embodiment the dispensing device comprises means for enhancing therapeutic fluid absorption into the systemic circulation by prompting vasodilatation of subcutaneous blood vessels. 
     In another aspect, the invention contemplates a system and/or a device for delivering therapeutic fluid to a body of a patient comprising a dispensing unit including a reservoir for retaining the therapeutic fluid, a driving mechanism to dispense the therapeutic fluid from the reservoir to the body of the patient, a controller to control, at least in part, operation of the driving mechanism, a power source to power at least the driving mechanism and the controller; and an absorption enhancement device for increasing the absorption rate of the therapeutic fluid in the body of the patient. 
     In one embodiment of the invention, the system further comprises a first subcutaneously insertable element for delivering the therapeutic therethrough to the body of the patient. In a preferred embodiment, the subcutaneously insertable element is a cannula. In a more preferred embodiment, the absorption enhancement device comprises at least one electrode disposed on the cannula, the electrode being capable of heating the local surrounding tissue i.e., the tissue surrounding the at least one electrode. 
     In another embodiment of the invention, the system comprises a first and a second subcutaneously insertable element. The first subcutaneously insertable element used to deliver the therapeutic therethrough to the body of the patient. The second subcutaneously insertable element having at least one electrode disposed thereon capable of heating local surrounding tissue. 
     Wherein the invention contemplates the use of one or more electrodes, the electrodes would generally be electrically connected to a power source, and the controller would control the driving mechanism to deliver the therapeutic fluid to the body and the at least one electrode to heat the local surrounding tissue, although separate controllers could be used to control the therapeutic fluid delivery and the at least one electrode. 
     In a further aspect of the invention, the system may comprise a dispensing unit including at least one housing, wherein the absorption enhancement device comprises one or more heating plates disposed on the at least one housing to heat the patient&#39;s skin surface. 
     In some embodiments, the system further comprises a skin adherable cradle unit that contains the absorption enhancement device and wherein the absorption enhancement device includes one or more heating plates to heat the patient&#39;s skin surface. 
     In another embodiment of the system of the invention, the absorption enhancement device further comprises a first and a second subcutaneously insertable element. The first subcutaneously insertable element is being used to deliver the therapeutic fluid therethrough to the body of the patient. The second subcutaneously insertable element is being used to deliver a chemical absorption enhancing agent such as a vasodilator (also referred-to as “vasodilatory agent”). In an alternative embodiment, a single subcutaneously insertable element can be used to deliver both the therapeutic fluid and the vasodilatory agent. In a preferred embodiment, the subcutaneously insertable element or elements comprise one or more cannulae, the cannulae having one or more lumens. The vasodilatory agent may be delivered in any number of methods. In one embodiment, the vasodilatory agent is delivered through the use of one or more micro-needles. 
     The vasodilatory agent may be retained in the dispensing unit of the system of the invention in either the same reservoir as the therapeutic fluid or in a separate second reservoir. 
     The system of the invention may also comprise a cradle unit having a plurality of wells to receive a plurality of subcutaneously insertable elements. In one embodiment, the cradle unit has a plurality of micro-openings to receive an array of micro-needles. 
     In another aspect, the absorption enhancement device of the system of the invention comprises a vibration mechanism capable of vibrating in a high frequency causing an increase of therapeutic fluid absorption rate in the body. 
     In another aspect, the absorption enhancement device of the system of the invention comprises an energy emitting source. The energy emitting source may take many forms including but not limited to a system for emitting UV energy, IR radiation, and/or acoustic waves. 
     In one embodiment, the systems described above can further include one or more sensors for monitoring tissue properties corresponding with the change in therapeutic fluid absorption rate. The sensor or sensors can take any number of forms including but not limited to a thermometer to measure temperature, a radiation detector, a pressure sensor, an acoustic sensor, and a chemical sensor measuring concentration level of an agent. 
     In a further embodiment, the controller of the system controls the operation of the absorption enhancement device based on one or more signals received from the sensor. 
     In another aspect the system of the invention, the system further comprises an analyte sensing device, such as a glucometer or a continuous glucose monitor (CGM), or a device that senses another analyte of interest. In a preferred embodiment, the analyte sensing device sends a signal to the system&#39;s controller and the controller controls the absorption enhancement device based on the signal. 
     The therapeutic agent or drug that the system delivers can be any therapeutic fluid. In a preferred embodiment the therapeutic agent is insulin. The vasodilatory agent also can be any number of compounds including but not limited to one or more of the following, alone or in combination: nitroglycerin, nitroprusside, histamine, PDE5 inhibitors, sildenafil, and papaverine. 
     In another aspect, the invention contemplates a method of enhancing absorption of a pharmaceutical agent or drug comprising applying an absorption enhancing stimulus to a drug administration site, and administering the drug to a subject in need of the drug. In a preferred embodiment, the absorption enhancing stimulus is applied locally to the drug administration site. Although various drugs and absorption enhancing agents are contemplated, in a preferred embodiment the drug is insulin. 
     The absorption enhancing agent may be applied prior to, after or at the same time as the administration of the drug. In a preferred embodiment, the absorption enhancing agent is applied prior to administration of the drug. 
     Although the method of the invention contemplates various modes of drug administration (e.g., transdermal, subcutaneous etc.), in a preferred embodiment, the method of the invention contemplates subcutaneous administration of the drug. 
     The absorption enhancing agent may take many forms including the direct application of heat using thermal electrodes, the application of ultrasonic energy, high frequency vibration, the application of electrical current, and/or chemical means such as a chemical vasodilator. Additionally, the absorption enhancing agent may be applied at various locations local to the drug administration site (e.g., transdermally, subcutaneously etc.). In a preferred embodiment, the absorption enhancing agent is heat (i.e., thermal energy). In a more preferred embodiment, the heat is applied subcutaneously. 
     According to one embodiment of the present invention, vasodilatation of subcutaneous blood vessels can be achieved by local heating of the injection site. The heating element (i.e., thermal electrodes, high frequency vibrator, etc.) can reside subcutaneously disposed on the cannula, on additional designated heating probe, or above the skin connected to the dispensing patch unit or cradle unit. 
     According to another embodiment of the present invention, vasodilatation of subcutaneously located blood vessels can be achieved by electrical current application. The electrical charge (i.e., current*time, Q=I*t, for example—2-15 mC) can be applied transcutaneously or subcutaneously by virtue of electrodes disposed on the surface of the subcutaneously insertable cannula. Alternatively, electrodes can be disposed on a subcutaneously located probe dedicated solely for providing current induced vasodilatation. According to one embodiment, a segmented current application is applied which has better vasodilatation effect than “at once” charge delivery. (Journal of Physiology 2002, 540(1), 261-269). The vascular response to galvanic current application is suggested to rely on an axon reflex and neurogenic inflammation with either anodal or cathodal current. The axon reflex-related cutaneous vasodilatation relies on the local release of neural primary afferent fibers mediators such as calcitonin gene-related peptide, substance P, and prostaglandin (Am J Physiol Heart Circ Physiol 2005, 288:668-673). 
     According to another embodiment of the present invention, vasodilatation of subcutaneous blood vessels can be achieved by application of laser that emits radiation in the UV spectrum range. Application of the UV laser beam may be either continuous or pulsed. Use of a pulsed laser reduces heat built-up and subsequent damage to the tissue. According to one such embodiment, the UV radiation wavelength is in the range of 150-400 nm. 
     According to another embodiment of the present invention, vasodilatation of subcutaneously located blood vessels can be achieved by concomitant administration of vasodilating pharmacologic agents (e.g., nitroglycerin, nitroprusside, histamine, PDE5 inhibitors). Alternatively the vasodilating pharmacologic agent is delivered prior to, or immediately after, the administration of the therapeutic fluid (e.g., insulin). Administration of the vasodilating pharmacologic agent can be done via the same cannula used for delivery of the therapeutic fluid (e.g., insulin) or via a dedicated cannula/probe. Alternatively, delivery of the vasodilating pharmacologic agent can be done by virtue of an may of microneedles that merely penetrate the stratum corneum layer of the skin. 
     According to one embodiment, administration of the vasodilating pharmacologic agent can be provided transdermally (i.e., topical application or transdermal patch). 
     According to one embodiment of the present invention, vasodilatation of subcutaneously located blood vessels can be achieved by a combination of any of the methods described in the abovementioned embodiments. 
     According to one embodiment of the present invention, enhancement of therapeutic fluid (e.g. insulin) absorption is performed only when bolus dosages are administered. According to one such embodiment, enhancement of therapeutic fluid (e.g. insulin) absorption is performed only when bolus dosages greater than a certain threshold value are administered. 
     The invention further contemplates a method of administering a therapeutic fluid to a body of a patient comprising providing (a) a dispensing device including a reservoir retaining the therapeutic fluid, a driving mechanism to dispense the therapeutic fluid from the reservoir to the body of the patient; and (b) an absorption enhancement device which causes an increase in the absorption rate of the therapeutic fluid in the body of the patient. The absorption enhancement device is initiated and the therapeutic fluid or drug is administered to the body of the patient. 
     In one embodiment, the method of administering the therapeutic fluid comprises inserting a cannula into the body of the patient, the cannula including the absorption enhancement device. The therapeutic fluid is preferably delivered through the cannula. 
     In another aspect of the invention, the method of administration contemplates that the absorption enhancement device includes a heater, and wherein the method comprises the initiation of the absorption enhancement device includes controlling the heater to locally elevate the temperature in surrounding tissue. In a preferred embodiment, at least part of the absorption enhancement device is located subcutaneously. In a more preferred embodiment, the therapeutic fluid administration and temperature elevation occur substantially in the same insertion site. 
     In another aspect of the invention, the method of administration comprises the administration of a vasodilatory agent to the body of the patient. 
     In yet another aspect of the invention, the method of administration includes inserting a first subcutaneously insertable element into the body of the patient to deliver the therapeutic fluid therethrough, and inserting a second subcutaneously insertable element having the absorption enhancement device. 
     In another aspect of the invention, the method of administration may include the further step of monitoring a change corresponding to the therapeutic fluid absorption rate, which may or may not be used to control (directly or indirectly) either therapeutic fluid delivery and/or therapeutic fluid absorption enhancement. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  shows curves of blood glucose and insulin levels over time after a meal intake and an insulin bolus, and the lag period between glucose and insulin blood levels peaks. 
         FIG. 2  illustrates an exemplary fluid delivery device according to some embodiments of the present disclosure. The device is composed of dispensing unit and remote control unit. 
         FIG. 3  shows the insulin infusion device comprising a dispensing unit and a remote control unit. The dispensing unit contains a means for enhancing therapeutic fluid absorption according to some embodiments of the invention. 
         FIGS. 4 a -4 c    illustrate the attachment of the dispensing unit to a skin securable cradle unit. 
         FIG. 5  is a block diagram representing the rationale behind incorporating a vasodilatation means in an insulin infusion device. 
         FIG. 6  shows a dispensing patch unit comprising a means for enhancing subcutaneous insulin absorption by local heating of the injection site with electrodes disposed on the surface of the subcutaneously inserted cannula. 
         FIGS. 7 a -7 c    illustrate the inferolateral aspect of the dispensing patch unit connected to the cradle unit, and the cannula coated with a heating electrode. 
         FIGS. 8 a -8 c    illustrate another embodiment of the inferolateral aspect of the dispensing patch unit connected to the cradle unit, and the cannula coated with a heating electrode. 
         FIG. 9  shows a dispensing patch unit comprising a means for enhancing subcutaneous insulin absorption by local heating of the injection site by electrode/electrodes disposed on a designated subcutaneous element. 
         FIGS. 10 a -10 b    illustrate the inferolateral aspect of a dispensing patch unit connected to a cradle unit, a drug delivery cannula, and a subcutaneous element with a heating electrode. 
         FIGS. 11 a -11 b    show two embodiments of a dispensing patch unit comprising a means for enhancing subcutaneous insulin absorption by local transdermal heating of the injection site. 
         FIGS. 12 a -12 b    illustrate the inferolateral aspect of a cradle unit comprising a heating electrode which serves as a means for enhancing subcutaneous insulin absorption by local transdermal heating of the injection site. 
         FIGS. 13 a -13 b    illustrate inferolateral aspect of a dispensing patch unit comprising a heating plate in the Reusable Part of the dispensing patch (RP), and a cradle unit  20  with an opening aligned with the RP heating plate. 
         FIG. 14  illustrates another embodiment of a dispensing patch unit comprising a means for enhancing subcutaneous insulin absorption by local transdermal heating of the injection site. 
         FIGS. 15 a -15 b    show the inferolateral aspect of the patch unit that contains an annular heating plate, and a cradle unit with an opening aligned with the patch unit heating plate. 
         FIGS. 16 a -16 b    show two different embodiments of a dispensing patch unit provided with means for enhancing subcutaneous insulin absorption by administration of a vasodilating pharmacologic agent. 
         FIGS. 17 a -17 b    illustrate the inferolateral aspect of the dispensing patch unit connected to the cradle unit, the cannula through which insulin is delivered, and the cannula through which a vasodilatory agent is delivered. 
         FIGS. 18 a -18 b    illustrate another embodiment in which the insulin and the vasodilatory agent are delivered through one double lumen cannula. 
         FIG. 19  shows a dispensing patch unit provided with means for enhancing subcutaneous insulin absorption by administration of a vasodilating pharmacologic agent via a dedicated array of microneedles. 
         FIGS. 20 a -20 b    show the inferolateral aspect of the patch unit with an array of micro-needles arranged around the outlet port, and a cradle unit that contains dedicated openings aligned with the microneedles in the patch unit. 
         FIG. 21  shows the remote control unit with GUI showing data of insulin dose administration and vasodilatory agent administration. 
         FIG. 22  shows the remote control unit with GUI indicating vibration as a means for achieving local heating for enhancement of therapeutic fluid absorption. 
         FIGS. 23 a -23 b    illustrate a transdermal patch unit that can deliver at least one local vasodilator agent. 
         FIGS. 24 a -24 d    illustrate topical administration of a vasodilatory agent as a means for enhancing insulin absorption. 
         FIGS. 25 a -25 d    show four different embodiments of a dispensing patch unit  10  comprising a component capable of enhancing subcutaneous insulin absorption by electrical current application. 
         FIGS. 26 a -26 d    show four different embodiments of a dispensing patch unit comprising means for enhancing subcutaneous insulin absorption by laser that emits light in the UV range. 
         FIG. 27  is detailed schematic description of a two-part patch unit employing a peristaltic pumping mechanism. 
         FIG. 28  is a schematic cross-sectional view of a two-part patch unit. 
         FIGS. 29A-29B  are transverse cross-sectional views depicting connection of a patch unit to and disconnection of the patch unit from a cradle unit. 
     
    
    
     DETAILED DESCRIPTION 
       FIG. 2  illustrates a fluid delivery device  1000  for medical infusion of therapeutic fluid(s) (for example—insulin), into a body of a patient. The device  1000  comprises a dispensing unit  10  and a remote control unit  900 . The dispensing unit  10  comprises a means for enhancing subcutaneous absorption of the delivered fluid  70 . 
       FIG. 3  shows an insulin infusion device  1000  according to some embodiments of the invention comprising a dispensing patch unit  10 , which can be secured to the user&#39;s skin  5 , and a remote control unit  900 , which communicates with the dispensing patch unit  10 , allowing programming, user inputs and data acquisition. 
     In one embodiment, the patch unit comprises a driving and pumping mechanism (either separately provided or integral with one another), a reservoir and an exit port. The patch unit may comprise a reservoir, a driving mechanism such as an electrical DC or stepper motor, a shape memory alloy actuator, or the like and/or a pumping mechanism such as a peristaltic pump, a syringe, or the like. The patch unit may also comprise a power supply means and electronic components. The patch unit can be composed of one part or two parts, namely a reusable part and a disposable part and can be connected to and disconnected from the needle unit. In some embodiments, the needle unit comprises a penetrating member with connected thereto cannula, well and cradle. 
     The patch unit  10  can be connected to a cannula  6  that penetrates the skin  5  to allow delivery of insulin to a patient. The patch unit  10  can be attached to a dedicated cradle unit  20  that is a flat sheet adhered to the user&#39;s skin  5  and allows connection/disconnection of the patch unit  10 . An exemplary embodiment of this arrangement is discussed in a co-owned, A 2 co-pending U.S. patent application Ser. No. 12/004,837, the disclosure if which is hereby incorporated by reference in its entirety. 
     Manual inputs can be carried out by one or more buttons  1011  located on the dispensing patch unit  10 . The dispensing patch unit  10  can be composed of one housing or two housings comprising reusable  100  and disposable 200 parts as shown in our previous patent application U.S. Ser. No. 11/397,115 and International Patent Application PCT/IL09/000,388, the disclosures of which are hereby incorporated by reference in their entireties. 
     In accordance with the invention, a means for enhancing subcutaneous insulin absorption  70  is incorporated within the patch unit  10 . The absorption enhancing means  70  can be incorporated in the disposable part  200 , reusable part  100 , cradle unit  20 , cannula  6 , or any combination of the abovementioned parts and/or units. 
       FIGS. 4 a -4 c    illustrate a fluid delivery device that includes a cradle unit  20  that can be adhered to the skin  5  of the user. The dispensing unit  10  can then be connected to and disconnected from the cradle unit  20  upon patient&#39;s discretion.  FIG. 4 a    illustrates the cradle unit  20  adhered to the skin  5 .  FIG. 4 b    illustrates the connection of the dispensing unit  10  to the cradle unit  20 .  FIG. 4 c    illustrates the dispensing unit  10  connected to the cradle unit  20  and ready for operation. 
     In accordance with the invention, a means for enhancing subcutaneous insulin absorption  70  is incorporated in the dispensing patch unit  10 . The absorption enhancing means can alternatively (not shown) be incorporated in the cradle unit  20 , the cannula (not shown), or any combination of the abovementioned parts and/or units. 
       FIG. 5  is a block diagram representing the rationale behind incorporating a vasodilatation means in an insulin infusion device. The initial step  400  of local vasodilatation (also referred-to as “vasodilation”), which can be achieved in a variety of methods as detailed in the following figures, is followed by insulin delivery, at step  401 , to a locally vasodilated subcutaneous tissue. At step  402 , enhanced insulin absorption is obtained, consequently leading to a faster reduction of high blood glucose at step  403 , and to better glycemic control immediately and in the long run  404 . An optional mechanism for the enhanced insulin&#39;absorption is that the increased blood flow obtained by the vasodilatation in step  400  raises the concentration gradient across the blood vessel and therefore enhances absorption by passive diffusion. Vasodilatation achieved by local heat generation may also cause enhanced absorption by increasing vessel wall permeability and drug solubility. 
       FIG. 6  shows a dispensing patch unit  10  comprising a means for enhancing subcutaneous insulin absorption by local heating of the injection site by heating at least one electrode  15  disposed on the surface of the subcutaneously inserted cannula  6  through which insulin is delivered. The heating electrode/electrodes  15  serve as electrical heaters. Electrical energy is provided by a power supply  240 , located in the DP  200 , and transmitted via wires and connectors  155 , located in the DP  200  and cradle unit  20 , to at least one heating electrode  15  which converts the electrical energy to heat. The power supply  240  may alternatively be located in the RP (not shown). Temperature can be controlled using variable resistors, and duration and quantity of the power supplied. 
       FIG. 7 a    illustrates the inferolateral aspect of the dispensing patch unit  10  connected to the cradle unit  20 , and the cannula  6 , coated with at least one heating electrode  15 , that penetrates through a “well”  210  of the cradle unit. The well  210  is a protrusion that encircles a passageway enabling the insertion and placement of the cannula in a subcutaneous compartment of the user&#39;s body and rigidly anchoring the cannula.  FIG. 7 b    is a magnification of the portion of  FIG. 7 a    depicting the electrode  15  coated cannula  6  protruded through the well  210  of the cradle unit  20 .  FIG. 7 c    illustrates a transverse section of the cannula  6  and heating electrode  15 . The electrode  15  in  FIGS. 6 a - c    is limited to a partial length and circumference of the cannula. 
       FIG. 8 a    illustrates the inferolateral aspect of another embodiment of the dispensing patch unit  10  connected to the cradle unit  20 , and the cannula  6 , coated with a heating electrode  15 , penetrating through a well  210  of the cradle unit.  FIG. 8 b    is a magnification of the portion of  FIG. 8 a    depicting the electrode  15  coated cannula  6  protruded through the well  210  of the cradle unit  20 .  FIG. 8 c    illustrates a transverse section of the cannula  6  and circumferential heating electrode  15 . The electrode  15  in  FIGS. 7 a - c    covers the entire length and circumference of the cannula, thus allowing smoother insertion of the cannula through the well, and a larger and more symmetric area of local heating. 
       FIG. 9  shows a dispensing patch unit  10  comprising a means for enhancing subcutaneous insulin absorption by local heating of the injection site, wherein local heating is achieved by heating of at least one electrode  15  disposed on a designated subcutaneously located element  67 . The dispensing patch unit  10  comprises proximal, subcutaneously located cannula for insulin delivery  6  and element  67  for mounting the heating electrode/electrodes  15  used for enhancing insulin absorption. Electrical energy is provided by a power supply  240 , located in the DP  200 , and transmitted via wires and connector  155  to the heating electrodes  15  which serve as electrical heaters which convert the electrical energy to heat. The power supply  240  may alternatively be located in the RP (not shown). 
       FIG. 10 a    illustrates the inferolateral aspect of the dispensing patch unit  10  connected to the cradle unit  20 , the cannula  6  through which insulin is delivered, and the element  67  coated with at least one heating electrode  15 . Both cannula  6  and element  67  penetrate through dedicated wells,  210  and  210 ′ respectively.  FIG. 10 b    is a magnification of the portion of  FIG. 10 a    depicting electrode covered element  67  and cannula  6  penetrating through the bottom of the cradle unit. 
       FIGS. 11 a - b    show two embodiments of a dispensing patch unit  10  comprising a means for enhancing subcutaneous insulin absorption by local transdermal heating of the injection site. 
     In  FIG. 11 a    electrical energy is provided by a power supply  240 , located in the DP  200 , and transmitted via wires and connectors  51  to at least one heating plate  45  located in the cradle unit  20 . The skin  5  located directly beneath the cradle unit is thus exposed to the heat generated by the heating plate  45 . 
     The power supply  240  may alternatively be located in the RP (not shown). 
     In  FIG. 11 b    the heating plate  45  is located in the RP  100 . A cavity  28  in the cradle unit  20  located directly beneath the heating plate  47  provides better heat transfer from the heating plate  47  in the RP to the underlying skin  5 . Wires and connectors  52  located in the RP  100  and in the DP  200  allow electrical energy transfer from the power supply  240  in the DP  100  to the heating plate  47  in the RP  100 . Alternatively (not shown), the power supply is located in the RP. Alternatively (not shown) the heating plate is located in the DP  200  and the cavity in the cradle unit is aligned with the location of the heating plate in the DP. 
       FIGS. 12 a - b    illustrate the inferolateral aspect of a cradle unit  20  comprising a heating electrode  45  which serves as a means for enhancing subcutaneous insulin absorption by local transdermal heating of the injection site. In  FIG. 12 a    the heating plate covers a relatively large proportion of the bottom surface of the cradle unit. In  FIG. 12 b   , the heating plate  46  is circumferential to the cannula  6  that penetrates through the well of the cradle unit  20 . Such a rounded heating plate provides annular, symmetrical heat distribution around the cannula  6 . 
       FIG. 13 a    illustrates the inferolateral aspect of a dispensing patch unit  10  comprising a heating plate  47  in the RP  100 .  FIG. 13 b    illustrates the cradle unit  20  with a opening  28  aligned with the expected location of the heating plate in the RP, once the patch unit is connected to the cradle unit. 
       FIG. 14  illustrates another embodiment of a dispensing patch unit  10  comprising a means for enhancing subcutaneous insulin absorption by local transdermal heating of the injection site. The heating plate  44  in  FIG. 14  is arranged concentrically around the outlet port  213  of the DP  200 . Such a rounded heating plate provides annular, symmetrical heat distribution around the cannula  6  through which the insulin is delivered. Electrical energy transfer from the power supply  240  in the DP  100  to the heating plate  44  by virtue of electrical wires. Alternatively (not shown), the power supply is located in the RP, and the electrical energy is transferred via wires and connectors between the RP and the DP. 
     An opening  24  in the cradle unit  20  located directly beneath the heating plate  44  provides better heat transfer from the RP to the underlying skin  5 . The opening  24  in the cradle unit may be segmented as to hold the base of the cradle unit and the well in one piece. 
       FIGS. 15   a - b  show the inferolateral aspect of the patch unit  10  with the annular heating plate  44  around the outlet port  213 , and the cradle unit  20  with the dedicated segmented opening  24  aligned with the heating plate in the patch unit  10 .  FIG. 15 a    shows the cradle unit  20  and patch unit  10  disconnected.  FIG. 15 b    shows the two parts connected. The heating electrode  44  is exposed by virtue of the segmented opening  24  in the cradle unit  20  once the two parts are assembled. 
       FIGS. 16 a - b    show two different embodiments of a dispensing patch unit  10  provided with the capability of enhancing subcutaneous insulin absorption by concomitant administration of a vasodilating pharmacologic agent (e.g. nitroglycerin, nitroprusside, histamine, PDE5 inhibitor). The vasodilating pharmacologic agent is alternatively delivered prior to, or immediately after, the administration of the therapeutic fluid (e.g. insulin). The insulin and the vasodilatory agent have different reservoirs  3  and  33  respectively, and different delivery tubes. 
     In  FIG. 16 a    the vasodilatory agent is delivered via a dedicated cannula  66 , and the dispensing patch unit  10  comprises two proximal, subcutaneously located cannulae; one for insulin delivery  6  and one for vasodilatory agent delivery used for enhancing insulin absorption. In  FIG. 16 b    the vasodilatory agent and the insulin are delivered via the same cannula  6 . The dose, rate, and timing of delivery of both pharmaceutical agents (i.e. insulin, vasodilator agent) can be controlled by the user. 
       FIG. 17 a    illustrates the inferolateral aspect of the dispensing patch unit  10  connected to the cradle unit  20 , the cannula  6  through which insulin is delivered, and the cannula  66  through which a vasodilatory agent is delivered. Both cannulae  6 ,  66  penetrate through dedicated wells,  210  and  210 ′ respectively.  FIG. 17 b    is a magnification of the portion of  FIG. 17 a    depicting the two cannulae  6 ,  66  penetrating through the bottom of the cradle unit  20 . 
       FIG. 18 a    illustrates another embodiment in which the insulin and the vasodilatory agent are delivered through one double lumen cannula  6 . One lumen  7  is dedicated for insulin delivery and the other lumen  8  is dedicated for delivery of a vasodilatory agent.  FIG. 18 b    is a cross section of the double lumen  7 ,  8  cannula  6 . 
       FIG. 19  shows a dispensing patch unit  10  provided with the capability of enhancing subcutaneous insulin absorption by administration of a vasodilating pharmacologic agent (e.g. nitroglycerin, nitroprusside, histamine, PDE5 inhibitor) via a dedicated array of microneedles. The therapeutic agent (e.g. insulin) and the vasodilatory agent have different reservoirs,  3  and  33  respectively, and different delivery tubes. The insulin reservoir  3  is connected to a cannula  6  and the reservoir containing the vasodilatory agent  33  is connected by a secondary reservoir  34  which is in direct connection with an array of microneedles  311 . According to the embodiment, the microneedles are arranged concentrically around the cannula  6 , and the secondary reservoir  34  is a ringed shape tube and the microneedles  311  extend downward therefrom. The cradle unit  20  comprises dedicated micro-openings  310  through which the microneedles  311  penetrate. According to another embodiment (not shown) the cradle unit comprises a segmented hollow opening through which the microneedles can easily penetrate (i.e., opening in the cradle unit for the entire array of microneedles rather than micro-openings for each microneedle). The microneedles  311  penetrate only the outermost layer of skin  5  that contains no nerve endings, and thus avoid causing pain during insertion and at the same time avoid the mechanical barrier presented by the outer layer of the epidermis the stratum corneum. 
       FIGS. 20 a - b    show the inferolateral aspect of the patch unit  10  with the array of microneedles  311  arranged around the outlet port  213 , and the cradle unit  20  with the dedicated openings  310  arranged around the well  210  and aligned with the microneedles  311  in the patch unit  10 .  FIG. 20 a    shows the cradle unit  20  and patch unit  10  disconnected.  FIG. 20 b    shows the two parts connected. The microneedles  311  penetrate through the openings  310  once the two parts are assembled. 
       FIG. 21  shows the remote control unit  900 , with navigating buttons  904 , showing data of insulin bolus dose administration  906  and vasodilatory agent administration  910  in an insulin delivery device (not shown) provided with the capability of enhancing subcutaneous insulin absorption by administration of a vasodilating pharmacologic agent. 
     According to one embodiment of the invention, local heating of the subcutaneous tissue can be obtained by local high frequency vibration, as can be seen in the GUI of the remote control unit  900  illustrated in  FIG. 22 . The ‘vibrate’ option is indicated with numeral  902 . According to one such embodiment, vibration can be achieved by ultrasound acoustic energy—a modality commonly used in physiotherapy to achieve deep tissue warming. 
       FIGS. 23 a  and 23 b    illustrate a transdermal patch unit that can deliver at least one local vasodilator agent. Transdermal patches are commonly used to deliver pharmaceutical materials percutaneously. Transdermal patches are generally layered structures, with the skin-facing layer comprising an adhesive having microholes. Above this adhesive layer is a medication containing layer, and a waterproof cover layer is generally provided. The adhesive serves to attach the patch to the skin and the medication in the central layer is provided to the skin through the microholes in the adhesive layer. Slow and controlled release of the medication may be achieved by such transdermal patches. 
       FIG. 23 a    shows the cradle unit  20  that comprises, at least in part, an adhesive layer  111  to securely attach the cradle unit  20  to the patient&#39;s skin. The adhesive  111  should be biocompatible (e.g. does not stimulate irritation) and comfortable to the patient without disturbing his/her diurnal routine. Before adhesion a protective peelable cover layer (not shown) should be removed from the adhesive. According to the embodiment, a vasodilator containing layer may be disposed on the adhesive layer  111 . The adhesive layer  111  may contain microholes  201 . The distribution of the microholes  201  on the adhesive layer may determine the skin area affected by the drug. According to one embodiment, the microholes can be located only in the immediate circumference of the cannula through which the insulin is delivered. The transdermally delivered vasodilator, contained in the patch unit, may be any one or more of the known in the art transdermally delivered vasodilators such as nitroglycerine, papaverine, and prostaglandin E1. According to one embodiment, transdermal vasodilatation using 10 milligrams of phentolamine mesylate dissolved in 0.23 mL of alcohol may be used, as detailed in U.S. Pat. No. 6,007,836 which describes a system for producing and maintaining male erection by transdermal administration of a vasodilating agent.  FIG. 23 b    illustrates the patch unit  10  connected to the cradle unit with vasodilator bound adhesives  111 . 
       FIGS. 24 a -24 d    illustrate topical administration of a vasodilatory agent as a means for enhancing insulin absorption. In  FIG. 24 a   , the cradle unit  20  attached to the user&#39;s skin is shown to comprise a cavity  22  through which the skin is exposed. 
       FIG. 24 b    shows wipes  26  comprising a topical vasodilatory agent.  FIG. 24 c    shows the user topically applying the vasodilatory agent  26  to the exposed skin, in the vicinity of the cannula, showing through the cradle unit  20 .  FIG. 24 d    shows the patch unit  10  reconnected to the cradle unit  20  after topical application of a vasodilating agent. The user may disconnect the patch from the cradle unit  20  and apply the topical vasodilator agent (possibly using the wipes depicted in  FIG. 24 b   ) only before a bolus is administered. 
       FIGS. 25 a - d    shows four different embodiments of a dispensing patch unit  10  comprising a component capable of enhancing subcutaneous insulin absorption by current application. According to one such embodiment, an electrical charge of 2-15 mC is applied. According to one embodiment, a segmented current application is applied. A segmented current application results in a peak vasodilatation superior to the one observed following a current of comparable total charge delivered all at once (Journal of Physiology 2002, 540(1), 261-269). The vascular response to galvanic current application is suggested to rely on an axon reflex and neurogenic inflammation with either anodal or cathodal current. The axon reflex-related cutaneous vasodilatation relies on the local release, from primary afferent fibers, of neural mediators such as calcitonin gene-related peptide, substance P, and prostaglandin (Am J Physiol Heart Circ Physiol 2005, 288:668-673) 
     In  FIG. 25 a - b    local vasodilation is achieved by applying the current directly in the subcutaneous tissue by virtue of at least two conduct electrodes  16  and  16 ′ disposed on the surface of a subcutaneously inserted cannula or probe. 
     In  FIG. 25 a    the conductive electrodes  16  and  16 ′ are disposed on the same cannula through which the therapeutic fluid is delivered  6 . Electrical energy is provided by a power supply  240 , located in the DP  200 , and transmitted via wires and connectors  155  to at least two electrodes  16 ,  16 ′ which generate a galvanic current in the subcutaneous tissue. In  FIG. 25 b    the electrodes  16 ,  16 ′ are disposed on a designated subcutaneously located element  67 . 
     In  FIG. 25 c    local vasodilation is achieved by transdermal current application. The electrodes  16  and  16 ′ are located in the cradle unit  20 . Connectors  155  located in the cradle unit  20  and in the DP  200  allow current supply from the power supply  240  in the DP  200  to the electrodes  16 ,  16 ′ in the cradle unit  20  via wires. 
     In  FIG. 25 d    local vasodilation is achieved by transdermal current application wherein the electrodes  16 ,  16 ′ are located in the RP  100  and openings  166  in the cradle unit  20  enable direct current transmission to the user&#39;s skin. 
       FIGS. 26 a - d    shows four different embodiments of a dispensing patch unit  10  comprising a component capable of enhancing subcutaneous insulin absorption by application of laser that emits light in the UV range. Application of the UV laser beam may be either continuous or pulsed. Use of a pulsed laser reduces heat built-up and subsequent damage to the tissue. According to one such embodiment, the UV light is in the range of 150-400 nm. 
     In  FIG. 26 a -26 b    local vasodilation is achieved by application of laser that emits light in the UV range, wherein the light source is on the surface of a subcutaneously inserted cannula or probe. Electrical energy is provided by a power supply  240 , located in the DP  200 , and transmitted via wires and connectors  155  to at least at least one light source  17  which emits light in the UV range in the subcutaneous tissue. 
     In  FIG. 26 a    the light source  17  is located on the same cannula through which the therapeutic fluid is delivered  6 . 
     In  FIG. 26 b    the light source  17  is located on a designated subcutaneously located element  67 . 
     In  FIG. 26 c    local vasodilation is achieved by transdermal UV light application. The light source  17  is located in the cradle unit  20 . Connectors  155  located in the cradle unit  20  and in the DP  200  allow current supply from the power supply  240  in the DP  200  to the electrode  16  in the cradle unit  20  via wires. 
     In  FIG. 26 d    local vasodilation is achieved by transdermal UV light application wherein the light source  17  is located in the RP  100  and an opening  177  in the cradle unit  20  enables direct light transmission to the user&#39;s skin. 
       FIG. 27  shows (via  FIGS. 27A and 27B ) a two-part patch unit  10  comprised of a reusable part  100  and a disposable part  200 . Reusable part  100  may comprise manual buttons/switches  105 , positive displacement pump provided with rotary wheel  110 , driving mechanism  120  and/or electronic components  130 . Disposable part  200  may include a reservoir  220 , delivery tube  230 , energy supply means  240  and/or stator  290 . The disposable components are used until emptying of the reservoir  220 . Rotation of the wheel and pressing of rollers against the stator  290  periodically positively displaces fluid within the delivery tube  230  by virtue of a peristaltic motion. An example of suitable positive displacement pump is disclosed in commonly owned application U.S. Ser. No. 11/397,115, which is hereby incorporated by reference. Driving mechanism  120  is provided (e.g. a stepper motor, a DC motor, a SMA actuator or the like), which rotates the rotary wheel and is controlled by electronic components residing in the reusable part  100  of the patch unit  10 . Among such electronic components can be controller, processor and/or transceiver. The electronic components are schematically designated by a common numeral  130 . An appropriate power supply  240  is also provided, which may include one or more batteries. Infusion programming can be carried out by a remote controller (not shown) having a bidirectional communication link with the transceiver provided in the patch unit  10 . Alternatively or additionally, the infusion programming can be carried out by manual buttons/switches  105  provided on the patch unit  10 . 
     As depicted by  FIG. 28 , lateral notches  12  may be provided on exterior sides of both parts. Before connecting the patch unit  10  with the cradle unit  20  the disposable  200  and reusable  100  parts are attached to each other and constitute the single patch unit  10  as seen in  FIG. 28 . 
       FIGS. 29A and 29B  show an example of connection and disconnection of the patch unit  10  comprised of a reusable part  100  and a disposable part  200 , and the skin-adherable cradle unit  20 .  FIG. 28  shows the two units before connection. When the patch unit  10  is brought into contact with the cradle unit  20  it is guided by the anchoring latches  302  maintaining precise alignment between the two units and anchoring of the two units.  FIG. 29A  shows the patch unit  10  after it has been connected to the unit  20  and secured due to snapping engagement of the anchoring latches  302  provided at the outside periphery of the unit  20  with the lateral notches  12  provided at the patch unit  10 .  FIG. 29B  shows the patch unit  10  being disconnected by back-pulling the elastically deformable latches  302 . Also illustrated are: the subcutaneously insertable element in the form of a cannula  6 , an absorption enhancement device in the form of a heating plate  44 , the well  210 , and the user&#39;s skin  5 . 
     Any and all references to publications or other documents, including but not limited to, patents, patent applications, articles, webpages, books, etc., presented in the present application, are herein incorporated by reference in their entirety. 
     Although a few variations have been described in detail above, other modifications are possible. For example, the logic flow depicted in the accompanying figures and described herein do not require the particular order shown, or sequential order, to achieve desirable results. 
     While the present invention has been described in terms of specific methods, structures, and devices it is understood that these are example embodiments only and that variations and modifications will occur to those skilled in the art upon consideration of the present invention. As well, the features illustrated or described in connection with one embodiment can be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present invention. Those skilled in the art will appreciate, or be able to ascertain using no more than routine experimentation, further features and advantages of the invention based on the above-described embodiments. Accordingly, the invention is not to be limited by what has shown and particularly described, except as indicated by the appended claims particularly. 
     All publications and references are herein expressly incorporated by reference in their entirety. The terms “a” and “an” can be used interchangeably, and are equivalent to the phrase “one or more” as utilized in the present application. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.