Patent Publication Number: US-9415163-B2

Title: System for controlled administration of a substance from a human body-implanted infusion device

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is the US national stage of International Application PCT/IT2010/000319 filed on Jul. 20, 2010. 
     FIELD OF THE INVENTION 
     The present invention generally regards the controlled administration of substances through infusion devices implanted in the human body and more particularly has as object a system for the controlled administration of a substance such as a drug, a hormone or a hormone complex and the like for which other administration modes result unsatisfactory or ineffective. 
     STATE OF THE ART 
     Pathological conditions are known which require extended administration over time (also over the entire life of the patient) of substances adapted to compensate for the shortage or absence of those normally produced endogenously, or adapted to supply active principles against chronic diseases. Such administration occurs through infusion devices that are partially or totally implanted in the human body. For example, a pathological condition which requires this type of treatment is diabetes. 
     Many diabetes types are currently known. The main ones are
         Type 1   Type 2   Gestational Diabetes       

     Diabetes mellitus type 1 is characterized by a shortage of insulin production by the beta cells of the Islets of Langerhans in the pancreas, often due to the destruction of these cells following an autoimmune attack by T lymphocytes. Currently, practically all the individuals who suffer diabetes mellitus type 1 must be subjected to daily injections of exogenous insulin, which constitute the most widespread and common remedy but which considerably limit the possibility of diabetes subjects to live a normal life. Non-insulin treatments, based on monoclonal antibodies and stem cell treatments, are effective on animal models, but have not yet passed the clinical trial phase on human individuals. Type 2 diabetes is characterized by an increase of the glycemia in the blood due to a double effect: that of insulin-resistance and that of a deficit of insulin secretion. These two effects can coexist, or they can present themselves separately and/or subsequently. Gestational diabetes is present in certain subjects during pregnancy and causes hyperglycemia due to the incapacity of the maternal pancreas to secrete a sufficient amount of insulin to oppose the effect of the hormones produced by the placenta, which have an opposite effect with respect to insulin itself. 
     In order to allow diabetic patients to automatically control their glucose level in the blood, it was proposed to substitute the endocrine functionality of the natural pancreas with a device generally known as artificial pancreas. The medical introduction of the artificial pancreas is relatively recent (A M Albisser et al.: Clinical control of diabetes by the artificial pancreas,  Diabetes,  23(5):397-404, 1974), but up to now a long-term implantable system has not been identified. There are fairly complete and advanced devices in the literature which attempt to confront this technological problem, but no solution at the moment appears resolutive. 
     An important element of an implantable pancreas is the pump for the release of insulin. Among the various types of pumps and their different implant locations, the most interesting are those which release insulin in the peritoneal cavity, reaching the portal vein. From here, the insulin immediately stops the hepatic production of glucose, effectively emulating the functionality of the beta cells in controlling glycemia. This technological problem was resolved and the first implantable insulin pump prototype appeared in Europe in 2000. The insulin reserve is sufficient for 3 months, after which the device is explanted and resupplied with insulin, as well as new batteries (J L Selam: External and implantable insulin pumps: current place in the treatment of diabetes,  Exp Clin Endocrinol Diabetes,  109:333-340, 2001). On the basis of this device, other more sophisticated pumps were developed, but they too must be periodically resupplied, making their long-term implantation impossible. An infusion pump of this type was placed on the market by Minimed (USA). This pump is made of titanium and has a weight of 150 g, releases insulin in the peritoneal cavity and is remotely controlled by the patient. The tank has a capacity of 15 ml and must be periodically refilled by means of transcutaneous insulin injections, an invasive and irritating procedure which the user has a hard time accepting. 
     Recently, much more advanced prototypes and commercial products provide for the coupling of external insulin pumps with a transcutaneous catheter, coupled with advanced glycemic sensors (implanted or otherwise) and with advanced control algorithms. Such systems, even if considerably improved from the standpoint of the glycemia monitoring and insulin release control, have not solved the problem of long-term implantability. 
     In substance, the problem is how to resupply the insulin and energy device without having to surgically operate on the patient. An adequate solution has not yet been found for this problem. In addition, none of the known devices is completely mini-invasive: the presence of catheters or other transcutaneous structures naturally limit the freedom of movement and life of the user. 
     An important element for making an autonomous device is the presence of a glycemic sensor which continuously supplies data relative to the concentration of glucose in the blood. Notwithstanding the intrinsic technical difficulties associated, numerous systems exist today for the continuous monitoring of the glycemia. 
     Such systems continuously measure the glucose concentration in the interstitial fluids, through needle-shape sensors (T M Gross et al.: Efficacy and reliability of the continuous glucose monitoring system,  Diab Tech  &amp;  Therap,  2:19-26, 2000; S K Garg et al.: Improved glucose excursions using an implantable real-time continuous glucose sensor in adults with type 1 diabetes,  Diab Care,  27(3):734-738, 2004; R Jamali et al.: Continuous glucose monitoring system signals the occurrence of marked postprandial hyperglycemia in the elderly,  Diab Tech  &amp;  Therap,  7(3):509-515, 2005) or through a micro-dialytic fiber (T C Dunn et al.: Rates of glucose and change measured by blood glucose meter and the glucowatch biographer during day, night, and around mealtimes,  Diab care,  27(9):2161-2165, 2004). The supposition that the glucose concentration in the interstitial liquids is comparable to that of the hematic side is assumed to be well-grounded. The lag time for the balancing between the two compartments has been estimated to be around 4-10 minutes. In order to have more reliable glycemic data, above all in real time, it is necessary to employ implantable sensors which detect the data directly from the blood flow. 
     An ideal artificial pancreas model should combine the most physiological insulin infusion mode with the most accurate glycemia monitoring system, characterized by the least lag time. The insulin infusion which allows best imitating the function of the beta cell is undoubtedly intraperitoneal insulin infusion (IIP). The advantages of IIP are due to the release of insulin directly into the peritoneal cavity, which allows quickly reaching the portal circulation and hence reproducing physiological insulinization conditions. 
     It was also shown that the glucose monitoring system characterized by the shortest lag time is the subcutaneous continuous monitoring system of the glycemia and not the intravascular monitoring of the glucose. 
     An implantable closed-loop system MIP-XS has been proposed in the literature (Renard et al.: Artificial β-cell: clinical experience toward an implantable closed-loop insulin delivery system,  Diab  &amp;  Metab,  32(5):497-502, 2006). The system comprises a pump and a catheter for the insulin release, a glycemic sensor connected to the pump and an integrated control algorithm. An external device is capable of receiving the data. Nevertheless, also in this system it is not possible to resupply the insulin tank and the batteries from the outside. 
     Recently (September 2009), Medtronic presented a new device, called “Paradigm Veo System”, at the annual meeting of the International Society for Pediatric and Adolescent Diabetes (ISPAD). Such device is capable of automatically suspending the insulin release when the glucose levels fall below a threshold fixed by the user. The device comprises a pump for the insulin and a continuous monitoring system of the glucose levels (by means of a sensor and a transmitter). The patient reads the glycemic progressions directly on the monitor and occasionally checks them by using the glycemia measurement strips, then he/she programs the micro-infuser to release the appropriate amount of insulin. However, if the data transmitted by the sensor show that the glucose levels have fallen below a limit fixed by the patient, the device emits an alarm signal, and if this alarm is ignored, the insulin pump automatically blocks the release of insulin up to a maximum of two hours. However, neither does this system provide for a system that is totally implantable and of long duration. 
     Artificial pancreas structures are for example described in WO2004/014254, and JP2002085556. 
     The object of the present invention is to provide a system for the controlled administration of a substance through an infusion device implanted in the human body which solves the problems encountered in the prior art and does not require surgical operations for carrying out periodical resupplying of the substance to be administered or the substitution of the batteries which supply power to the device. 
     One particular object of the present invention is to provide a system of the abovementioned type applied to the treatment of diabetes. 
     Another object of the present invention is to provide a system of the abovementioned type in which the resupplying of the substance to be administered is carried out by means of ingestion of a carrier containing a pre-established volume of said substance. 
     A further object of the present invention is to provide a system of the abovementioned type in which the energy recharging of the battery which supplies power to the device is carried out from the outside, in a non-invasive manner. 
     Another object of the present invention is to provide an intelligent carrier of the substance to be administered, suitable for being ingested, in order to transport the substance to the implant site and transfer it to the infuser device. 
     SUMMARY OF THE INVENTION 
     These and other objects are achieved with the system for the controlled administration of a substance according to the present invention whose essential characteristics are reported in claim  1 . 
     Other important characteristics are reported in the dependent claims. 
     According to one aspect of the invention, a system is provided for the controlled administration of a substance via an infusion device implanted in the human body, comprising an implantable unit for detecting a shortage or an excess of the substance, an infusion group of this substance implantable in the peritoneal cavity and comprising a central control unit for processing data received by the detection unit in order to generate command signals for the release of the substance in the intraperitoneal cavity, as well as energy storage means for powering the infusion group. The system also comprises a carrier of the substance adapted to be ingested in order to passively reach the duodenal lumen and made of perforable material resistant to gastric acids, with parts made of magnetizable metal, and a recharge device for resupplying said substance to said infusion group comprising a magnetic reversible docking group for said carrier facing on the duodenal lumen and actuable when the carrier reaches a predetermined distance therefrom, and means for drawing the substance from the carrier communicating with suction means of the infusion group. 
     According to another aspect of the invention, an ingestible device is provided for transporting a substance to a site of the gastrointestinal tract where an infusion device of said substance is implanted, comprising a body made of gastro-resistant material and perforable, defining a chamber within which the substance is stored, means sensitive to an attraction force generated by a magnetic field arranged on the body surface and means for generating a proximity signal adapted to provide an indication on its distance from the infusion device. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Further characteristics and advantages of the system for the controlled administration of a substance according to the present invention will be apparent from the following description of an exemplifying and non-limiting embodiment thereof, made with reference to the attached drawings in which: 
         FIG. 1  illustrates the general architecture of the system for the controlled administration of insulin according to the present invention; 
         FIG. 2  schematically shows an implantable insulin infusion group employed in the system according to the present invention; 
         FIGS. 3 a  and 3 b    illustrate an insulin capsule employed in the system according to the invention, with an end cap removed shown in  FIG. 3   b;    
         FIG. 4  shows an implantable docking device for the insulin capsule of  FIGS. 3   a,b;    
         FIGS. 5 a , 5 b , 5 c    illustrate the steps of approach, docking, and release of the insulin capsule of  FIGS. 3   a,b;    
         FIGS. 6 a , 6 b    illustrate the deactivated and activated condition, respectively, of the docking device of  FIG. 4 . 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In the following detailed description of the invention, reference is made to the case in which the substance to be administered in a controlled manner is insulin, but it is clear that the described system is also applicable when a substance of different type has to be administered. 
     With reference to  FIG. 1 , the system for the controlled administration of insulin according to the present invention comprises an infusion group  100  comprising a pump  101  for the infusion of the insulin into the peritoneal cavity and an insulin tank  102  communicating with said pump, and an insulin refilling device  103  for the periodic resupplying the tank  102  with insulin. An outlet duct  104  extends from the pump  101  and leads into the intraperitoneal cavity for the insulin delivery. The infusion group  100  also comprises a central control unit  105  for controlling the functioning of the infusion group  100  and a main battery  106  which provides the necessary power for the functioning of the infusion group  100 , the refilling device  103  and the central control unit  105 . The central control unit  105  also comprises a wireless communication unit  107  (e.g. of ZigBee type or RFID type). The infusion device  100  with the relevant central control unit  105  and the battery  106 , together with the refilling device  103 , form a miniaturized mechatronic unit, indicated with IAP (Implantable Artificial Pancreas) in  FIG. 1 , implantable in the peritoneal zone, behind the stomach and near the duodenum, in substitution of, or close to, the endocrine part of the original pancreas, preferably by means of a laparoscopic operation. 
     The infusion group  100  cooperates with a glycemia sensor  200 , also implanted, which continuously transmits the detected glycemia rate data to the central control unit  105 . A wireless communication from central control unit  105  to an external control unit  300 , preferably of portable type, is provided. 
     The system also comprises an external battery-charger  400 , e.g. mounted on a belt or other wearable support, for the periodic wireless recharging of the battery  106  and a swallowable insulin carrier  500 , for example a capsule containing insulin, adapted to periodically transport an insulin refill from the outside to the infusion group  100 . 
     The implantable unit IAP is schematically shown in  FIGS. 2 and 4 . It is implanted and surgically fixed in the anatomic zone of the pancreas; it therefore physically as well as functionally substitutes this organ. Alternatively, it can be positioned close to the organ, if the latter still has residual functions. 
     As shown in  FIG. 2 , the infusion group  100 , the central control unit  105  and the main battery  106  are arranged in a closed and sterile casing  108 . An inlet duct  109  exits from the casing  108  to be connected with the insulin refilling device  103 , described below. The duct  109  passes through a filter  107 , e.g. with 0.2 micron pores, which sterilizes the insulin entering into a vacuum pump  110 , actuable by a motor  111 . In  FIG. 2 , the central control unit  105  is also shown along with the main battery  106 , which respectively control and power all the actuators of the system. 
     From the vacuum pump  110 , the insulin is transferred to the tank  102  by means of an inner duct  121  and from here to the pump  101  for the controlled release of the insulin, whose motor  112  is activated by the central control unit  105  only when the implanted glucose sensor  200  signals a glycemic rate greater than a pre-established value. Before the insertion in the peritoneal cavity through the duct  104 , the insulin passes through a further filter, not shown, for the complete sterilization, essential for avoiding any risk of anaphylactic shock. 
     The outlet duct  104  exiting from the infusion pump  101  is an artificial channel which allows the connection of the infusion device  100  with the peritoneal cavity and is constituted by a small tube which is at least externally covered by a biocompatible material (e.g. silicone). The inlet duct  109  is connected to a needle  120  (means for drawing a substance), shown in  FIGS. 4 and 5 , intended to cross the duodenal wall at an orifice provided with a unidirectional (non-return) valve  123 , shown in  FIG. 5 , surgically inserted and sutured on the wall of the duodenum, once the refilling device  103  (described below) has begun the procedure for connecting with the insulin capsule  500 . 
     The glycemia detection unit  200  comprises an implanted subcutaneous glycemia sensor, for example the CGMS Gold of Medtronic Minimed, Inc. (USA), capable of continuously monitoring the rate of glucose present in the interstitial fluids, and a wireless communication system (RFID or ZigBee), assisted by a local battery, for the transmission of the information from the sensor to the central control unit  105 . 
     According to the present invention, in order to periodically refill the implanted tank  102  with insulin, the use of an intelligent insulin carrier  500  is provided, e.g. in the form of a capsule containing an insulin refill, which, once ingested by the patient, travels through the digestive tract passively, i.e. without its own locomotion means, until it arrives at the duodenum, where it reaches the refilling device  103  of the implanted tank  102 . 
     As shown in  FIG. 3 a   , the insulin capsule  500  is formed by a substantially cylindrical body  501  delimiting an internal chamber, within which the insulin is stored. In particular, the capsule has a diameter not greater than 15 mm and length not greater than 25 mm. The capsule is made of polymer material resistant to gastric acids, but mechanically yielding in a manner such that it can be easily perforated by the refilling device  103 . On the body  501  two metal rings  502  are provided for, possibly covered by a layer of the same polymer material for improving the biocompatibility, since the metal, directly in contact with the body fluids, could release ions. As shown in  FIG. 3 b   , inside the capsule  500 , a wireless communication device  503  is housed, such as a RFID tag, associated with a local battery  504 , adapted to communicate continuously its own distance to another analogous receiving device of the central control unit. 
     The refilling device  103  comprises a docking group  113  which surfaces inside the duodenum and the needle  120  supported by the group  113  in an axially movable manner for the perforation of the housing  501  of the insulin capsule  500 . 
     As shown in  FIG. 4 , the docking group  113  comprises a motor  114 , preferably a stepping motor, encoder-controlled, connected via a gear transmission  115  to a magnet  116  with lateral magnetization inserted in a ferromagnetic housing  117  including two elements  118  of non-ferromagnetic material which interrupt its continuity. The magnet  116  is connected to one of the gears  115  by means of a shaft, not shown, that permits it to rotate following the activation of the motor  114 . The ferromagnetic housing  117  has two pole pieces  117   a  and  117   b  whose ends are facing inside the duodenal lumen. 
     The magnet  116  is arranged between the two non-ferromagnetic elements  118 , so that when the poles of the magnet are turned towards them, as shown in  FIG. 4 , the field lines are shut from north to south ( FIG. 6 a   , deactivated condition) on a short path passing through the close ferromagnetic material, and there are no magnetic field lines outside. By rotating the magnet  116  by 90°, its poles are separated from the two non-ferromagnetic elements  118 , through which the magnetic field lines cannot pass. The preferential path then becomes the longer path through the ferromagnetic part of the housing  117  ( FIG. 6 b   , activated condition) and this results in a corresponding polarization of the ends  117   a  and  117   b  facing in the duodenal lumen. 
     With reference to  FIGS. 5 a , 5 b  and 5 c   , when the insulin capsule  500  reaches the duodenal lumen, approaching the point where the infusion group  100  is implanted, it transmits a position signal through its wireless communication device  503  to the central control unit  105 . The latter commands the activation of the docking group  113 , after which the motor  114  imparts a rotation of 90° to the magnet  116  and a magnetic field is established at the ends  117   a  and  117   b  of the housing  117 . The magnetic field attracts the insulin capsule  500  thereto due to the presence of the two metal rings  502  on its body  501 . Advantageously, the ends  117   a  and  117   b  have form complementary to the ends of the capsule, in a manner so as to receive the capsule and keep it in position due to the magnetic attraction force on the metal rings  502  of the capsule. In particular, the two ends have a hollowed form with radius substantially equal to that of the body  501 . 
     On the housing  117  of the docking device a linear motor  119  is arranged, adapted to move the needle  120  axially following a command received by the central control unit  105 , after the capsule  500  has attached itself to the docking group  113 . The success of the docking operation is monitored by contact sensors (not shown) present on the ends  117   a  and  117   b , which communicate to the central unit  105  that the docking has taken place. The needle  120  is in communication with the vacuum pump  110  through the duct  109  connected to the vacuum pump  110 . During its advancement, the needle  120  crosses through the intestinal wall, indicated with IW in the  FIGS. 5   a,b,c , at the unidirectional valve  123  sutured on the intestinal wall which prevents the reflux of liquids or solids from the intestinal lumen towards the interior of the peritoneal cavity. When the needle  120  has perforated the body  501  of the capsule  500 , the central unit  105  activates the vacuum pump  110  by means of the motor  111  and the insulin contained in the capsule is transferred into the tank  102  ( FIG. 5 b   ). Once the transfer of the insulin is completed, for example signaled by a level sensor in the tank, the needle is extracted and returns to the initial position, the unidirectional valve is consequently closed and the magnet is deactivated, allowing the separation of the capsule which can continue on its path in the digestive tract ( FIG. 5 c   ) until its expulsion. 
     The main battery  106 , like the local battery of the glycemia detection unit  200 , is provided with a wireless recharge system of substantially known type based on the principles of electromagnetic induction, externally activable via coupling of suitable solenoids or similar structures. In particular, lithium polymer batteries or lithium ion batteries are employed. The recharge device  400  is configured for being positioned close to the implanted organ by attaching it, for example, to a belt or another wearable support. 
     The central control unit  105  processes the data coming from the glycemic sensor  200  and commands the release of a proper amount of insulin at a certain speed into the intraperitoneal cavity, the object being that of imitating the functionality of the healthy pancreatic beta cells as best as possible. The control algorithm employed is based on the proportional, integral and derivative scheme (PID) or on algorithms derived therefrom. 
     The amount of insulin to be infused, provided by the controller of PID type, is described by the equation: 
     
       
         
           
             
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     The parameters K P , K I , and K D  are respectively the proportional, integral and derivative coefficients, and G and G B  represent the current glycemia and the basal glycemia. The derivative component produces the typical response of the first phase of the pancreatic beta cells, while the integral component produces the second phase. 
     The central control unit also provides for the monitoring of the insulin level present in the tank  102  of the infusion group  100  and the residual battery level, and transmits this information to the external control unit  300  in a wireless manner through its communication unit  107 . 
     The external control unit  300  is preferably of portable type, and more preferably wearable, like a watch. It receives signals and data from the glycemia detection unit  200  and from the implanted central control unit  300  and comprises a display on which the glycemia level and the operations performed by the system to correct it (e.g. intraperitoneal infusion of a certain amount of insulin at a given instant) are shown in real time. The display also provides the indication of the insulin level present in the tank  102  and the residual battery level. 
     The external control unit also comprises an alarm device to alert the patient when the insulin volume falls below a certain threshold, and it is therefore time to ingest a capsule to refill the tank, or when the battery requires recharging. An internet connection may also be provided for in the external control unit for sending these signals to the attending physician or directly to the hospital, which is alerted and begins preparing the necessary operations for battery recharging or necessary insulin capsule refilling. 
     The components of the system are mainly achieved with biocompatible materials of known type, in order to assure its long-term implantability. 
     The system for the controlled administration of insulin according to the present invention makes available a fully artificial substitute of the natural pancreas, totally implantable in the body and biocompatible. The advantage with respect to conventional treatments, which provide for a series of daily insulin injections, is clear: the patient is not obliged to such irritating injections, which must be done at precise time intervals and which strongly condition his life. In addition, another advantage is the lower amount of insulin necessary with respect to conventional treatment, given its direct release in the peritoneal cavity, which causes a much greater absorption of the same with respect to the subcutaneous injections. 
     The pump  101  of the infusion group  100  releases insulin in the peritoneal cavity, simulating the functionality of the pancreatic beta cells as best as possible in controlling the glycemia. By means of intraperitoneal infusion, in fact, the pump, in addition to having a non-discontinuous infusion mode, allows the insulin to quickly reach the portal vein, and from here it immediately stops the hepatic glucose production. The particular anatomic location, moreover, allows the device a simple interfacing with the duodenum, which is found a few centimeters distant. 
     The few existing artificial pancreases, either partially or totally implantable, have two main defects: they either consist of parts which project outside the patient (e.g., they comprise portable apparatuses connected with small tubes which enter inside the body) or they require periodic substitutions/modifications. The first aspect strongly conditions the patient&#39;s lifestyle, since the latter is obliged to pay attention to the device at all times, making sure not to damage it. Sports activities, baths/swims etc. are limited by such factor. The second factor requires surgical operation each time the possible implanted device must be provided with new batteries or insulin. The advantages of the present invention are concentrated on these two aspects: by having an artificial pancreas that is totally implanted inside the body and in a zone protected by surrounding tissues, the patient can perform normal everyday activities, including playing sports, without worrying about the device. Such aspect is a considerable advantage, also at a psychological level and with regard to the acceptability of the device by the user. The other aspect, related to the periodic substitution/modification, is eliminated by the double solution: wireless recharge of the battery and refill of the insulin tank from outside the tank by means of ingestible capsules which transport a sufficient quantity for a prolonged use. 
     Even if the present invention has been described with particular reference to the case in which the substance to be administered is insulin, the case where the substance is different also falls within the scope of the present invention. In such case, the functioning of the system can be associated to a detection unit of a shortage or an excess of such substance or with the detection of a physiological parameter correlated with the shortage or excess of such substance. 
     Variations and/or modifications can be made to the system for the controlled administration of a substance according to the present invention, without departing from the scope of the invention as defined in the attached claims.