Abstract:
A capsule is capable of releasing at least one agent that is contained therein by heating at least one heating element under the effect of at least one alternating magnetic field at a defined point in a body, said capsule dissolving when entering in contact with a dissolving liquid. The capsule avoids getting stuck on stenoses while being thermally acceptable and favorable from the point of view of energy. In the capsule, the heating element is at least partially surrounded with a capsule part, material of which is provided with greater thermal resistance than the walls of common capsules used for medicaments.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     The invention relates to a capsule for releasing agents contained therein at defined points in a body, particularly useful for the examination of the digestive tract.  
         [0002]     It is a generally known fact that a significant part of all drugs is taken in the form of tablets or capsules containing agents that can be absorbed in the digestive tract. With the exception of the stomach, for which the application of medicaments is well managed, the precise location of the absorption could not be adjusted until now. An inherent disadvantage resides in the fact that the passage speed through the intestine and the pH value in the intestine varies considerably for different persons and even for a particular individual depending upon his/her condition. Therefore, even especially prepared capsules used for medicaments, e.g. time controlled, enzyme controlled, pH value controlled or pressure controlled capsules, imply the risk that the agent may pass the target area without being absorbed in a sufficiently large quantity. But, conversely, if intentional overdoses are used, there will be the risk of unintended side effects.  
         [0003]     In the past, a number of methods, arrangements and capsules have become known that were focused on the determination of the specific position of a medicament capsule in the intestine and, if the target position was reached, were implemented to release the agent via remote control; see Andrä, W. et al., A novel method for real-time magnetic marker monitoring in the gastrointestinal tract, Physics in Medicine and Biology 45: 3081-3093 (2000); Hemmati, A., The Site of Iron Absorption in the Gastrointestinal Tract, German Med. Mth., Vol. XIII: 569-573 (1968); DE 29 28 477 A1; Grönig, R., Computer-controlled drug release from small-sized dosage forms, Journal of Controlled Release 48: 185-193 (1997); U.S. Pat. No. 510,801 A; DE 19745 890 A1; U.S. Pat. No. 4,239,040 A; U.S. Pat. No. 5,279,607 A. Most of the capsules described in the aforementioned publications have at least one of the following disadvantages. First, they contain a hard cover. Thus, there is the risk that such capsules may get stuck on stenoses in the intestine and possibly have to be removed by operative surgery. According to the publication by Rösch, T et al., in Derzeitige klinische Indikationen der Kapsel-Endoskoopie (Current clinic indications of capsule endoskopy) in the German journal Zeitschrift für Gastroenterologie (Journal for gastroenterology) 40: 971-978 (2002), this danger can even exist if stenoses have not been registered during a previous x-ray examination. Additionally, the capsules mentioned include hard parts, such as metal springs, batteries and electronic components or circuits that can have a toxic effect if they contact the intestinal wall.  
         [0004]     These two aforementioned disadvantages can be avoided by means of the intestine therapy capsule manufactured according to DE 197 45 890 A1 and, in the same way, by an already suggested capsule with a rotating ball, if suitable substances are used. But these solutions suggest a disadvantage that is due to the mechanism of release. The release is achieved by heating up a partial volume of the capsule (hereinafter referred to as heating element) in an alternate magnetic field by magnetic losses or by friction losses to such a degree that an organic substance melts or the opening of the capsule is activated in another way. Here, the intestine content or the intestinal wall, or the liquid agent is positioned in the direct vicinity of the heating element. The thermal conductivity of this environment is so high that the increased heating of the heating element causes the dissipation of an increased amount of heat into the environment that therefore does not contribute to the temperature rise of the heating element.  
         [0005]     The maximally achievable rise in temperature is determined by the fact that the total power that is input by the alternating field is dissipated into the environment. According to the theory of thermal conduction, the maximally achievable rise in temperature is proportional to the input power and approximately reversely proportional to the thermal conductivity of the environment. The thermal conductivity of the environment for the capsules described is 0.2 W/(m-K) or higher. The thermal resistance between the heating element and the environment is on the order of 1 to 10 K/W. The selected input power of the alternate magnetic field must be sufficiently high to reach the desired maximum temperature despite the heat dissipation. The input power of the alternate magnetic field must not be as high as may be desired because, otherwise, an excessive heating of the patient can be caused by eddy current losses in the body tissue [Brezovich, I. A., Low frequency hyperthermia: capacitive And ferromagnetic thermoseed methods, Medical Physics Monographs 16: 82-111 (1988)].  
         [0006]     It is therefore the object of the present invention to avoid the described disadvantages in an capsule design in accordance with the invention directed to preventing the capsule from getting stuck on stenoses while endowing the same with thermally acceptable characteristics and favorable properties from the point of view of energy.  
       SUMMARY OF THE INVENTION  
       [0007]     The object of the present invention is achieved by a capsule for releasing at least one agent contained therein at defined positions in a body, which comprises capsule parts enclosing the capsule including at least one insulating capsule part, a material of which has a greater thermal resistance than an other of said capsule parts. At least one heating element at least partially surrounded by said at least one insulating capsule part is provided, wherein the capsule is openable by heating the at least one heating element under an effect of at least one alternating magnetic field. The capsule is dissolvable when entering in contact with a solving liquid. The thermal resistance of the capsule part(s) surrounding the heating elements(s) should be higher than the thermal resistance of the other capsule parts or of common capsules used for medicaments, at least by one order. The invention makes it possible that, on the one hand, all parts of the capsule consist of substances that disintegrate or dissolve when entering in contact with a liquid medium and, on the other hand, the capsule part designated as the heating element is surrounded by a cover that has a considerably greater thermal resistance than 10 K/W. The power required to reach the release temperature is reduced by adding a thermal insulation envelope. The heating generated under the influence of the alternate magnetic fields in at least one part of the capsule leads to a remote-controlled evaporation of an easily evaporating liquid disponed threrin. This liquid presses the agent (or several agents) out of the interior of the capsule, or it causes the capsule wall, which is comprised of parts, to burst. An advantageous embodiment of this invention contains a capsule part at least partially surrounding the heating element, which is closed against the agent by a wall, variable with respect to its position and/or its expansion.  
         [0008]     In a preferred embodiment, at least one heating element that contains a magnetic powder, e.g. Fe 3 O 4  (magnetite), is surrounded by a thermally insulating envelope. Said envelope can be double-walled, in which the walls consist essentially of water-soluble material, such as hard gelatin or sugar, and which are separated by a gas layer, e.g. air. As the whole capsule may only have a specific size to avoid difficulties when swallowing it, the thickness of this envelope is also reduced. Therefore, this thickness must be considered when comparing the thermal conductivity without and with this envelope. Ideally, the thermal resistance of the envelope is about 500 K/W, in relation to a normal medicament capsule of the same size of which the thermal resistance is about 10 K/W. Instead of the double-walled envelope it is also possible to use a porous envelope of water-soluble material with enclosed gas pockets. The thermal conductivity of such porous materials and the conductivity of air differ only slightly.  
         [0009]     The present invention will now be described in more detail by way of the following schematic examples. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0010]      FIG. 1  is a longitudinal section through capsule in accordance with an embodiment of the invention with a bag that can be bloated;  
         [0011]      FIG. 2  is a longitudinal section through an inventive capsule with a stamp;  
         [0012]      FIG. 3  is a longitudinal section through an inventive capsule with a movable dividing wall; and  
         [0013]      FIG. 4  is a longitudinal section through an inventive capsule with two heating elements and two dividing walls that can change their position. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0014]      FIG. 1  depicts a capsule  10 , which comprises two parts  11 ,  12  with a common geometric axis X-X that are hermetically connected with each other, nested, and for example made of hard gelatin. The open end of the bigger part  11  slides over the smaller part  12  and, in a two-dimensional bent area, the bigger part  11  being provided with a small opening  112  that is closed by a membrane  13  against the spontaneous escape of the agent  14  contained in the capsule  10 . Normally, the agent does not contain water. Alternative to use of a membrane  13  closure, the opening  112  can be made sufficiently small or have a valve design such that the spontaneous escape of the agent  14  is not possible under normal pressure conditions. The capsule part  12  is double-walled and provided with air or another suitable insulation material between the walls for purposes of heat insulation  15 . Capsule part  12  contains a thin-wall bag  17  made of latex or polyethylene and filled with a heating element  16 . The folded structure  171  of this bag  17  allows the enlargement of the volume of the heating element  16  by at least 1 cm 3  or to double the volume. In the example, the heating element  16  is made of a composition of about 40 Vol. % Fe 3 O 4 , the losses of which are about 1 J/kg in a magnetic reversal cycle, and of about 60 Vol-% ethyl alcohol that has a boiling point at 78° C. and evaporates at this temperature and its expansion generates a pressure in the capsule  10  that opens the opening  112  so that the agent  14  escapes to the outside. It is also possible to use another easily evaporating and biocompatible liquid instead of ethanol. The rise in temperature is caused by an alternate magnetic field, which is generated by an electric coil  18  in a commonly known manner, in combination with the Fe 3 O 4 components in the bag  17 .  
         [0015]     A thin layer (eg., film or foil)  19  of polyethylene, shellac or another suitable substance covering the whole capsule  10  protects the capsule  10  against decomposition in a water containing and/or enzyme containing environment, that is given, for example, in the intestinal tract. The opening  112  can also be arranged at another point of the capsule part  11 . Instead of the double-walled part  12 , it is also possible to use a component that contains gas pockets and is made of water-soluble material. Finally, the capsule  10  is neither bound to the embodiment shown in  FIG. 1  nor to the two-part design described with respect thereto. The position of the coil  18  is schematically illustrated, and is located outside the body during the application.  
         [0016]      FIG. 2  also depicts a capsule  10 , the parts  11  and  12  of which are held together by a foil (film)  19  that surrounds the entirety of capsule  10 , and which should not be between the nested parts, i.e., in the area  20 . In this area, a biocompatible lubricant, e.g. paraffin, can optionally be added between the two capsule parts  11 ,  12 . The heat-insulating part  12  includes bag  17  therein with heating element  16  that is located in the direct vicinity to the bent area  121  of part  12  and supports itself against the bent area  121  during the expansion of the heating element  16 . Additionally, the part  12  is provided with guide surfaces  122  for the supporting and sealing elements  211  of a stamp  21  that can move towards the axial direction marked by an arrow  212 . If the heating element  16  is heated in the manner described with reference to  FIG. 1 , the liquid in the heating element expands and presses the stamp  21  with the part  11  towards the direction indicated by the arrow  212 . The foil  19  is torn in the area  20  and the agent  14  is discharged to the outside, for example into the intestinal tract. The penetrating water or other liquid decomposes the parts  11  and  12  from the inside. Like the supporting elements  211 , the stamp  21  should be made of a water-soluble material.  
         [0017]      FIG. 3  again depicts a two-part capsule  10  with a part  12  that is filled with an insulation material  15  and which is slid axially into the part  11  that is provided with an opening  112 . Here, the part  12  is fixed by a foil  19 . Part  12  contains (preferentially without the bag  17  of  FIG. 2 ) an element  16  that acts like a heating element if an alternate magnetic field is applied from the outside. A movable diving wall  213  separates said element  16  from the agent  14  which takes up most of the part of the capsule interior. When heating the element  16 , element  16  expands, for example, to double the volume and presses onto the agent  14  in such a way that a membrane  13  that closes the opening  112  in the capsule part  11  is caused to burst. The agent  14  can escape via the opening  112  and the solvent, for all capsule parts including the dividing wall  213 , can flow in. Furthermore, the disclosure relative to  FIGS. 1 and 2  applies analogously to  FIG. 3 .  
         [0018]     In is noted that the dividing wall  213  that is movable in the capsule part  12  is not bound to the configuration shown in  FIG. 3 .  
         [0019]      FIG. 4  also includes a two-part capsule with the two adjoining parts  11  and  12  that are provided with insulation materials  151 ,  152 , and which therefore exhibit a greater thermal resistance than the other parts of the capsule. Each of the parts  11  and  12  contain elements  161  and  162  each that functions like a heating element if an alternate magnetic field is applied from the outside and which is separated from the agent  141  and  142  by a movable and/or expandable dividing wall  213  and  214 . If the corresponding elements are heated, they expand to double the volume for example and press the agents, possibly one after the other, to the outside through the openings  1121 ,  1122  that can be closed for example by a plug (a valve)  131 ,  132 . The heating elements  161  and  162  can be comprised of different materials or different compositions of easily evaporating liquids and magnetic oxide powders so that the evaporation takes place at different temperatures or for different power values of the alternate magnetic field. Furthermore, the agents  141  and  142  in the capsule parts  11 ,  12  can be different. These agents  141 ,  142  can also be prepared in such a way that the desired effect is only produced after their mixture. Within the capsule  10 , the unintended mixture of the two agents  141  and  142  can be avoided by a fixed dividing wall  215 .  
         [0020]     The described invention demonstrates advantage in comparison to the state of the art. Due to the much greater thermal resistance of the insulation of part  12 , the power of the alternate magnetic field supplied to the capsule  10  can be considerably less for the same intended maximum temperature, e.g. 78° C., than for the capsules without an insulation cover. Although the volume of the heating element becomes smaller due to the insulation, the required supplied power for the same maximum temperature is ideally less than 1% of the power that must be supplied for the capsule without thermal insulation. Another advantage is offered by the expandable bag  17  or a flexible and/or movable wall that closes the heating element  16  against the agent  14 . Such approach avoids the use of pistons and similar elements made of hard material. When heating the magnetic powder above the temperature of ebullition of the liquid contained in the heating element, said liquid will evaporate and the agent will be discharged after a short period of time. Thus, the point of time and the location of the agent application are much better defined in this invention than in the methods and arrangements known heretofore. It is even possible to apply the agent subsequently in several portions if the supplied alternate field power is measured out appropriately. The construction of the capsule  10  has the effect that after the discharge of the agent  14 , the water-containing intestinal liquid, for example, enters into the capsule  10  and decomposes the capsule parts  11 ,  12  or the hard gelatin stamp  21  from the inside. The other parts of the capsule (magnetic powder, polyethylene foil) can be easily ducted so that the remainder of the capsule do not get stuck on stenoses.  
         [0021]     The individual features or any combination thereof described in the invention and the figures are inclusive of, but not limiting of, the invention, which is defined by the claims.  
       LIST OF REFERENCE NUMERALS  
       [0022]      10  capsule  
         [0023]      11 ,  12  (capsule) parts  
         [0024]      13  membrane  
         [0025]      14 ,  141 ,  142  agents  
         [0026]      15 ,  151 ,  152  air, insulation material  
         [0027]      16 ,  161 ,  162  heating elements  
         [0028]      17  bag  
         [0029]      18  coil  
         [0030]      19  layer, foil  
         [0031]      20  area  
         [0032]      21  stamp  
         [0033]      111 , 121  bent zones  
         [0034]      112 ,  1121 ,  1122  openings  
         [0035]      122  guide surfaces  
         [0036]      131 ,  132  valves, plugs  
         [0037]      171  folded structure  
         [0038]      211  sealing and supporting elements  
         [0039]      212  arrow  
         [0040]      213 ,  214  flexible and/or movable dividing walls  
         [0041]      215  fixed dividing wall  
         [0042]     X-X axis