Patent Publication Number: US-2011048145-A1

Title: Dissolution testing apparatus for pharmaceutical preparations

Description:
The present invention relates to a dissolution testing apparatus, and the operation thereof, for pharmaceutical preparations, and more particularly, the present invention is directed to a dissolution test vessel that is suitable for use in a dissolution testing apparatus not requiring a constant temperature water bath. 
     BACKGROUND OF THE INVENTION 
     For oral pharmaceutical preparations, a dissolution test method is prescribed by the Japanese Pharmacopoeia, and the dissolution testing apparatuses that can perform this dissolution test method include dissolution test vessels that are heated without using a water bath. In a waterless apparatus, cylindrical heating means are typically provided around dissolution test vessels. It is therefore possible to eliminate the need for maintenance operations such as cleaning the constant temperature water bath and the need for preparatory time heating the water in the bath before the start of the dissolution test. 
     Moreover, a vibration generation source, such as a motor, that is required to circulate the water in the bath can be removed, and therefore an improvement in dissolution conditions also can be achieved. 
     In addition, a dissolution test is typically the final test performed on a sample pharmaceutical preparation to observe how the pharmaceutical preparation behaves in the body. It is therefore desirable to be able to easily observe any dissolution variations during testing from the exterior of the dissolution vessel, while controlling the temperature of the dissolution water in the test vessel at a stable test temperature range of 37±0.5° C., as near to a reference dissolution test temperature of 37° C., i.e. close to body temperature. 
     SUMMARY OF THE INVENTION 
     The present invention provides a dissolution testing apparatus having a dissolution test vessel that comprises a transparent vessel main body having a cylindrical portion, a dome-shaped bottom portion that is continuous with a lower end of the cylindrical portion, and a ring-shaped collar portion that projects radially outward from an upper end edge of the cylindrical portion, and a heat generation portion further comprising a transparent ring-shaped heat generating sheet member that is wrapped around an outer peripheral surface of the cylindrical portion so as to be held thereon in a freely detachable manner. The ring-shaped heat generating sheet member is formed from a transparent heat generating material and in which an upper side power feeding strip and a lower side power feeding strip are disposed, respectively. An observation window is formed in the intermediate region between the upper side power feeding strip and the lower side power feeding strip. 
     According to an aspect of the present invention, an embodiment of the dissolution test vessel includes a water temperature detector and a boiling detector. The water temperature and boiling detectors and the upper side and lower side power feeding strips are connected via terminals to a heat control block for the testing vessel. 
     According to another aspect the present invention, an embodiment of the heat generation portion includes a pressing sheet member that acts to further secure the heat generating sheet member to the dissolution test vessel. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a perspective view showing an embodiment of a dissolution test vessel according to the present invention; 
         FIG. 2  is a schematic perspective view illustrating a heat generating portion shown in  FIG. 1 ; 
         FIG. 3  is a schematic electric connection diagram showing in detail the constitution of a heating control block shown in  FIG. 1 ; 
         FIG. 4  is a signal waveform diagram illustrating a heating control operation performed on an energization phase control element by a system control unit shown in  FIG. 3 ; 
         FIG. 5  is a schematic sectional view illustrating the manner in which a water temperature detector is disposed; and 
         FIG. 6  is a perspective view showing a dissolution testing apparatus employing six of the dissolution test vessels shown in  FIG. 1 . 
     
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     An embodiment of the present invention will be described in detail below with reference to the drawings. 
     In  FIG. 1 , a reference numeral  1  denotes an overall dissolution test vessel in which a vessel main body  2  formed from glass or a transparent, chemically inactive material, as prescribed by the Japanese Pharmacopoeia, includes a cylindrical portion  2 A, a hemispherical dome-shaped bottom portion  2 B that closes a lower end surface of the cylindrical portion  2 A, and a ring-shaped collar portion  2 C that projects radially outward from a peripheral edge of an upper end surface of the cylindrical portion  2 A. 
     A strip-form heat generation portion  3  is wrapped around the entire periphery of an outer peripheral surface of the cylindrical portion  2 A of the vessel main body  2 . 
     As shown in  FIG. 2A , the heat generation portion  3  is transparent, and includes a heat generating sheet member  4 A constituted by a rectangular sheet-form transparent heat generating synthetic resin material formed into a ring shape, and an upper side power feeding strip  4 B 1  and a lower side power feeding strip  4 B 2  embedded in an upper end edge portion region and a lower end edge portion region of the heat generating sheet member  4 A, respectively. Thus, a heat generating current flows through an intermediate region, i.e. the part of the transparent sheet material between the upper side power feeding strip  4 B 1  and the lower side power feeding strip  4 B 2  of the heat generating sheet member  4 A, and as a result, surface heat is generated in the intermediate region. 
     The upper side power feeding strip  4 B 1  and the lower side power feeding strip  4 B 2  are respectively connected to power feeding terminals  4 E 1  and  4 E 2 , which are provided in upper portion positions on the outer peripheral surface of the vessel main body  2 , via respective power feeding lines  4 D 1  and  4 D 2 . 
     The upper side power feeding strip  4 B 1  is led to an upper end portion on one end edge of the heat generating sheet member  4 A and thereby connected to a cool side power feeding line  4 D 1 , while the lower side power feeding strip  4 B 2  is led from a lower side portion of the heat generating sheet member  4 A to the upper end portion along the other end edge and thereby connected to a hot side power feeding line  4 D 2 . 
     Accordingly, a heating current supplied between the power feeding lines  4 D 1  and  4 D 2  travels along the upper side power feeding strip  4 B 1  and the lower side power feeding strip  4 B 2  provided on the upper side edge and lower side edge of the power generating sheet member  4 A, respectively, whereby the heating current is distributed to various length direction parts of the ring-shaped heat generating sheet member  4 A. The current is dispersed to the intermediate surface region between the upper side power feeding strip  4 B 1  and the lower side power feeding strip  4 B 2 , and as a result, heat is generated over the entire intermediate surface region. 
     Hence, the heat generating sheet member  4 A can be heated substantially evenly as a surface heat generation source for heating the outer peripheral surface of the cylindrical portion  2 A of the vessel main body  2 , and since the intermediate region part that is subjected to surface heating is transparent, the intermediate region part forms an observation window  4 C through which dissolution variation in a pharmaceutical preparation in the interior of the vessel main body  2  can be observed from the exterior of the heat generating sheet member  4 A. 
     In this embodiment, as shown in  FIG. 2B , a cylindrical, transparent pressing sheet member  5  formed from a heat-shrinking synthetic resin material is provided around an outer side of the heat generating sheet member  4 A, which is disposed on the outer surface of the cylindrical portion  2 A of the vessel main body  2 , so as to cover the heat generating sheet member  4 A. 
     In a state where the heat generating sheet member  4 A is wrapped around the cylindrical portion  2 A of the vessel main body  2 , the pressing sheet member  5  is fitted onto the outside of the heat generating sheet member  4 A from the bottom portion  2 B side of the vessel main body  2  so as to overlap the heat generating sheet member  4 A. 
     In this state, heat treatment is applied to the pressing sheet member  5  from the outside, causing the pressing sheet member  5  to shrink such that a shrinkage force is generated in a direction corresponding to a circumferential direction. As a result, an inward radial pressing force is applied to the entire heat generating sheet member  4 A. 
     Thus, the entire heat generating sheet member  4 A is pressed and held by the pressing sheet member  5  so as to be wrapped around the outer surface of the cylindrical portion  2 A of the vessel main body  2 . 
     As the pressing sheet member  5 , a “Teflon (registered trademark) PFA Heat Shrink Tube” PKF-200-110B, manufactured by Packing Land Ltd., may be used. 
     As shown in  FIG. 3 , the power feeding terminals  4 E 1  and  4 E 2  are connected to connection terminals  10 A 1  and  10 A 2  that are provided on an inside surface of a heating control block  10 , which is fixed externally to an upper portion outer peripheral surface of the cylindrical portion  2 A, so as to oppose the cylindrical portion  2 A. 
     The heating control block  10  includes a system control unit  11  constituted by a microcomputer, and by controlling an energization angle of an energization phase control element  12  constituted by a TRIAC in accordance with a phase control signal S 1  output by the system control unit  11 , an alternating current obtained from a household power supply outlet by a power plug  13  is supplied to the power feeding terminals  4 E 1  and  4 E 2  of the heat generation portion  3  via the energization phase control element  12  and the connection terminals  10 A 1  and  10 A 2 . 
     In this embodiment, the power plug  13  is constituted by a three-terminal plug including an earth terminal. Hence, a household power supply having an alternating current voltage V 0  (100 V in this embodiment) is input into the heating control block  10  via an input terminal  14 . 
     As shown in  FIG. 4A , in the household power supply voltage V 0 , zero-cross is generated cyclically at timings t 0  when a power supply phase is 0° and 180°. A power supply cycle detection circuit ( FIG. 3 ) detects this zero-cross and transmits a zero-cross detection pulse PX to the system control unit  11  in the form of a zero-cross detection signal S 2 . 
     In this embodiment, when a water temperature detection signal S 4  indicates a much lower room temperature than the reference dissolution test temperature of 37° C., the system control unit  11  trigger-activates the energization phase control element  12  constituted by a TRIAC at the generation timing of the trigger pulse PX. As a result, as shown in  FIG. 4B , a heating current I 0  is supplied to the heat generation portion  3  in a phase range of 0 to 180° or 180 to 360° with respect to the phase of the household power supply voltage V 0 . 
     At this time, the heat generation portion  3  generates maximum thermal energy, and therefore the dissolution water in the vessel main body  2  is heated rapidly. 
     When, as a result, the temperature of the dissolution water approaches the reference dissolution test temperature of 37° C., the system control unit  11  retards a trigger phase of a trigger pulse P 1 , P 2  or P 3  for activating the energization phase control element  12  on the basis of the water temperature detection signal S 4  and in accordance with the increase in the temperature of the dissolution water, as shown in  FIG. 4C ,  4 D or  4 E, whereby a heating current I 1 , I 2  or I 3 , current values of which are progressively smaller, is supplied to the heat generation portion  3 . 
     At this time, the thermal energy generated by the heat generation portion  3  gradually decreases, and therefore the temperature increase rate of the dissolution water in the vessel main body  2  gradually decreases such that the dissolution water eventually reaches the reference dissolution test temperature of 37° C. 
     When the temperature of the dissolution water in the vessel main body  2  exceeds the reference dissolution test temperature of 37° C., on the other hand, the system control unit  11  performs control on the basis of the water temperature detection signal S 4  such that a trigger pulse is not applied to the energization phase control element  12 , and as a result, a heating current is not supplied to the heat generation portion  3 . 
     Hence, when the temperature of the dissolution water in the vessel main body  2  exceeds the reference dissolution test temperature of 37° C., the dissolution water radiates heat naturally without being heated, and therefore the temperature falls to or below the reference dissolution test temperature of 37° C. Accordingly, the system control unit  11  returns to the control state described above in relation to  FIGS. 4B to 4E . 
     Hence, the system control unit  11  can control the temperature of the dissolution water in the vessel main body  2  to the dissolution test temperature range of 37±0.5° C. prescribed by the Japanese Pharmacopoeia. 
       FIGS. 4B ,  4 C,  4 D and  4 E shows examples in which a heating current I 0 , I 1 , I 2  or I 3  is supplied to the power feeding terminals  4 E 1  and  4 E 2  of the heat generation unit  3  when the energization phase control element  12  constituted by a TRIAC is triggered by a power supply voltage V 0  having a phase of 0° or 180°, 30° or 210°, 90° or 270°, or 150° or 330°, respectively. 
     The temperature of the dissolution water in the vessel main body  2  is detected by a water temperature detector  25  disposed on an inside surface of the cylindrical portion  2 A of the vessel main body  2 , whereupon a water temperature detection output S 5  is applied to a temperature detection terminal  28  of the heating control block  10  via a water temperature detection signal line  26  and a detection output terminal  27 , in that order. 
     The water temperature detection output S 5  applied to the temperature detection terminals  28  is amplified by a buffer amplifier  29  having a bridge input differential constitution and then supplied to the system control unit  11  as the water temperature detection signal S 4 . 
     In this embodiment, as shown in  FIG. 5A , the water temperature detector  25  is fixed onto an adsorption permanent magnet  25 C, which is held on the inside surface of the cylindrical portion  2 A by adsorption, by attachment permanent magnets  25 B 1  and  25 B 2  that are fixed to adhesive layers  25 A 1  and  25 A 2  adhered to the outside surface of the cylindrical portion  2 A. 
     The attachment permanent magnets  25 B 1  and  25 B 2  are provided in accordance with the amount of dissolution water injected into the vessel main body  2  such that when the injection amount is 900 ml, the upper water level attachment permanent magnet  25 B 1  is provided in the position of an upper water level LV 2  corresponding to the injection amount, and the lower water level attachment permanent magnet  25 B 2  is provided in the position of a lower water level LV 1  corresponding to a case in which 500 ml of the dissolution water is injected. 
     Hence, when the dissolution water injected into the vessel main body  2  is at a high water level, a user adsorbs the adsorption permanent magnet  25 C to the attachment permanent magnet  25 B 1  at the upper water level LV 2 , as shown in  FIG. 5A , such that the water temperature detector  25  can detect the temperature of the dissolution water at the high water level. 
     On the other hand, when the dissolution water injected into the vessel main body  2  is at a low water level, the user adsorbs the adsorption permanent magnet  25 C of the water temperature detector  25  to the attachment permanent magnet  25 B 2  provided at the lower water level LV 1 , as shown in  FIG. 5B , such that the temperature of the dissolution water at the low water level can be detected correctly. 
     In this embodiment, a liquid crystal temperature display portion  30  is provided on the heating control block  10 , and the system control unit  11  displays the temperature of the dissolution water in the vessel main body  2 , detected in accordance with the water temperature detection signal S 4 , thereon so that the user can check the temperature easily. 
     Further, a heating operation display portion  31  constituted by an LED element is provided on a surface of the heating control block  10 , and when the temperature of the dissolution water in the vessel main body  2  is raised from room temperature to the reference dissolution test temperature of 37° C. in preparation for a dissolution test operation, a heating underway display  31 A constituted by a red LED is illuminated to notify the user that a heating operation is underway. 
     When the dissolution water in the vessel main body  2  is in a stable condition within the dissolution test temperature range of 37±0.5° C., on the other hand, a stable display  31 B constituted by a green LED is illuminated to notify the user that a stable heating operation condition has been established. 
     Further, a boiling detector  35  ( FIGS. 1 and 3 ) constituted by a thermistor is provided on the outer peripheral surface of the heat generation portion  3 , and a boiling detection output S 6  therefrom is input into the system control unit  11  as a boiling detection signal S 7  via a detection output terminal  36 , a temperature detection terminal  37 , and a buffer amplifier  38  having a bridge input differential constitution. 
     Hence, when the vessel main body  2  reaches an abnormally high temperature, the system control unit  11  detects the abnormally high temperature as boiling and informs the user thereof by generating a warning sound from a boiling alarm  39 . The system control unit  11  also interrupts the heat generation operation of the heat generation portion  3  by interrupting output of the phase control signal S 1 . 
     In  FIG. 3 , a reference numeral  22  denotes a direct current power supply for supplying a direct current power supply to each part of the heating control block  10 . 
     As shown in  FIG. 6 , the dissolution test vessel  1  constituted as described above is attached to an attachment substrate  42  of a dissolution testing apparatus  41 . 
     In the dissolution testing apparatus  41 , six attachment holes  44  are drilled into the attachment substrate  42 , which is fixed to a frame  43  so as to extend in a horizontal direction, and the cylindrical portion  2 A of the vessel main body  2  is inserted into and held in the six attachment holes  44  from above such that the collar portion  2 C contacts the attachment substrate  42 . Thus, simultaneous dissolution tests can be performed using the six dissolution test vessels  1  during a single dissolution test operation. 
     To start a dissolution test in the dissolution testing apparatus  41  using the six dissolution test vessels  1 , the user pours test dissolution water into the dissolution test vessels  1  attached to the attachment holes  44  in the attachment substrate  42  after moving a dissolution testing apparatus main body  46  upward along guide rails  45  of the frame  43 . 
     In this embodiment, 900 ml or 500 ml of dissolution water are poured into the vessel main body of the dissolution test vessel  1 . The user then lowers the dissolution testing apparatus main body  46  to a predetermined position such that a stirring paddle  47  is inserted into each dissolution test vessel  1  from above, whereupon heating of the heat generation portion  3  is begun. 
     At this time, the heating control block  10  provided on the vessel main body of each dissolution test vessel  1  starts to heat the dissolution water in the vessel main body  2  rapidly on the basis of a command from the dissolution testing apparatus main body  46  by causing the energization phase control element  12  to pass the heating current I 0  ( FIG. 4B ) having an energization phase of 0° or 180° through the upper side power feeding strip  4 B 1  and the lower side power feeding strip  4 B 2 . As a result, an energizing current applied to the heat generation portion  3  is phase-controlled on the basis of the water temperature detection signal S 4  from the water temperature detector  25  such that the temperature of the dissolution water reaches the reference dissolution test temperature of 37±0.5° C. 
     Thus, at the start of the dissolution test, while the temperature of the dissolution water in the respective vessel main bodies  2  of the six dissolution test vessels  1  attached to the dissolution testing apparatus  41  is controlled to the reference dissolution test temperature of 37±0.5° C. and the dissolution water is stirred by the stirring paddles  47 , a sample pharmaceutical preparation introduced into the vessel main body  2  from the dissolution testing apparatus main body  46  is steadily eluted into the dissolution water. 
     As regards the progress of the dissolution condition in each of the dissolution test vessels  1  at this time, since the heat generation portion  3  is formed from a transparent material and the observation window  4 C is provided between the upper side power feeding strip  4 B 1  and the lower side power feeding strip  4 B 2 , the user can observe the progress of the dissolution condition easily from the outside as the pharmaceutical preparation in the vessel main body  2  is dissolved into the dissolution water from a fragmented state. 
     During observation of the dissolution condition, the dissolution testing apparatus main body  46  extracts dissolution water automatically at predetermined time intervals via a water extraction pipe  48  inserted into each dissolution test vessel  1 , and therefore variation in the concentration of the pharmaceutical preparation eluted into the vessel main body  2  can be checked. 
     When the dissolution test is completed in relation to a single portion of the pharmaceutical preparation, the six dissolution test vessels  1  attached to the dissolution testing apparatus  41  are removed from the attachment substrate  42  and washed, whereupon the dissolution test vessels  1  are reattached to the attachment holes  44  in the attachment substrate  42  for the next dissolution test. 
     Hence, dissolution tests are performed repeatedly on a large number of pharmaceutical preparations using the same vessel main bodies  2 . However, when a defect occurs in relation to the heat generation portion  3  of one of the six dissolution test vessels  1  during this time, the user can perform the dissolution test using the same vessel main bodies  2  by detaching the heat generation portion  3  from the cylindrical portion  2 A of the defective dissolution test vessel  1  and wrapping a new heat generation portion  3  around the cylindrical portion  2 A. 
     As shown in  FIGS. 2A and 2B , the heat generating sheet member  4 A bent into a ring shape is wrapped around the cylindrical portion  2 A of the vessel main body  2 , and in this state, the heat-shrinking pressing sheet member  5  is provided to cover the periphery thereof. Thus, the heat generation portion  3  is pressed against and held on the cylindrical portion  2 A so as to be detachable from the outer peripheral surface of the vessel main body  2 . Hence, by performing a simple operation of cutting through the defective ring-shaped heat generation portion  3  in a vertical direction, for example, the heat generation portion  3  can be detached easily from the pressed and held state, and thus the heat generation portion  3  can be replaced. 
     The new heat generation portion  3  can then be wrapped around the outside of the cylindrical portion  2 A easily and with stability simply by fitting the new heat generation portion  3  onto the corresponding vessel main body  2  from the bottom portion  2 B side and applying heat thereto. 
     Hence, the user can continue to use the vessel main body  2  to which the defective heat generation portion  3  was attached, and therefore a dramatic improvement in the use efficiency of the vessel main body  2  can be achieved. 
     Incidentally, to replace the entire vessel main body  2 , authorization must be obtained from the Japanese Pharmacopoeia, and therefore, if the heat generation portion  3  cannot be replaced easily, the corresponding vessel main body  2  must be discarded together with the defective heat generation portion  3 . With the constitution described above, however, it is possible to replace only the defective heat generation portion  3  without replacing the vessel main body  2 , and therefore a dramatic improvement in use efficiency can be achieved. 
     Note that in the above embodiment, a case in which the dissolution test vessel  1  constituted as shown in  FIG. 1  is attached to the dissolution testing apparatus  41  having the six attachment holes  44  shown in  FIG. 6  was described. However, the dissolution test vessel  1  is not limited to this application, and similar effects to those described above can be obtained when the dissolution test vessel  1  is provided in a greater number than six, for example twelve, or a smaller number than six, for example one. 
     Further, in the embodiment described above, as shown in  FIG. 2 , the heat generation portion  3  is pressed against and held on the cylindrical portion  2 A of the vessel main body  2  by providing the pressing sheet member  5  formed from a heat-shrinking synthetic resin material so as to cover the heat generating sheet member  4 A and applying heat thereto. However, the heat generation portion  3  is not limited to this constitution, and as long as the heat generation portion  3  provided on the periphery of the cylindrical portion  2 A includes a ring-shaped sheet member that can be pressed against and held on the cylindrical portion  2 A by a shrinkage force thereof that acts in a direction corresponding to the circumferential direction, any overall constitution may be employed. 
     Furthermore, in the embodiment described above, the dissolution test vessel  1  is formed on the basis of prescriptions laid down by the Japanese Pharmacopoeia, but the dissolution test vessel  1  may be formed on the basis of prescriptions laid down by another pharmacopoeia, for example the US Pharmacopeia. 
     This dissolution test vessel maybe used in a dissolution test that is performed on a pharmaceutical preparation on the basis of a pharmacopoeia.