Abstract:
Methods and apparatus are disclosed for reducing the degradation of heat sensitive components contained in a medical substance during heat sterilization of a heat sterilizable container including a first chamber including a first amount of a first medical substance and a second chamber including a second amount of a second medical substance, the first amount being greater than the second amount. The method includes heating the heat sterilizable container to a first predetermined temperature for sterilizing the first and second medical substances, thermally insulating the second chamber during at least a portion of the heating of the heat sterilizable container to the first predetermined temperature, holding the heat sterilizable container at the first predetermined temperature for a first predetermined time period, and cooling the heat sterilizable container thereafter.

Description:
The present invention concerns a method and an apparatus for reducing the degradation of heat sensitive components in medical substances during heat sterilisation, wherein the medical substances are contained in a multiple chamber recipient that comprises a first chamber with a first medical substance and at least one second chamber with an amount of a second medical substance that is smaller than that of the first medical substance, and the multiple chamber recipient is heated to a predetermined temperature for sterilising the medical substances, is held at this temperature for a predetermined time period and is subsequently cooled. 
     The method can, for example, be utilised with multiple chamber recipients with medical substances for parenteral feeding/nutrition, however the method is in particular to be used with multiple chamber recipients that contain medical substances for generating a dialysis fluid for peritoneal dialysis. 
     TECHNICAL BACKGROUND 
     Currently, haemodialysis is mainly used for acute kidney failure while for chronic kidney failure, besides transplantation, haemodialysis and peritoneal dialysis are utilised. In the case of peritoneal dialysis, the abdominal cavity is repeatedly filled at intervals with a dialysis fluid that is then removed after a hold time. The dialysis fluid is generally a buffered ionic solution with an osmotic means, wherein currently glucose is mainly used as an osmotic means and lactate is mainly used as a buffer. In this way, urea and other substances normally removed from the kidneys and excess water can be removed from the body. These dialysis fluids are produced in factories, transferred to plastic bags of two to five liter capacity and sterilised, in a similar manner to solutions for parenteral nutrition. 
     A disadvantage of these dialysis fluids is the presence of degradation products. At present, it is assumed that during heat sterilisation these degradation products and the accompanying brownish colour of the fluid are produced by the glucose. It is further presumed that some of these degradation products are responsible for bioincompatability reactions generated by the dialysis fluid. Studies confirm that the degradation products react strongly with biological tissue and have a substantial effect on the immune system and the cells of the peritoneum, either alone or in combination with lactate and/or a low pH value. 
     Theoretically, the dialysis fluids could be rendered sterile by filtration in place of the heat sterilisation. In practice, however, this is not possible because essentially all countries stipulate that medical solutions must be sterilised by heat. 
     However, it is known that the degradation of glucose can be markedly reduced when the sterilisation temperature is increased and simultaneously the sterilisation time shortened. It is likewise known that the glucose degradation depends strongly on the pH value, and for example is at its lowest with a pH value between 3.0 and 3.5. However, a peritoneal dialysis fluid with such a low pH value is not permitted for the treatment of patients, for this a pH value of a little over 7 would be optimal, for example 7.1 to 7.4. As a compromise, therefore, a pH value of about 5.3 is set for conventional dialysis fluids. However, from a medical point of view, this is still too low and is probably the cause of infusion pain in some patients. Furthermore substantial amounts of degradation products are still generated during heat sterilisation, which is undesirable for the reasons already mentioned. 
     An improvement is proposed in WO 93/09820. In the dialysis fluid disclosed here, the glucose is isolated in a small separate second chamber from the rest of the dialysis fluid located in a first chamber. The glucose is separated in this second chamber with a high concentration and a low pH value, so that the formation of degradation products of glucose during heat sterilisation is substantially reduced. The pH value of the glucose in the separate second chamber is about 3.2, while the remainder of the solution in the larger chamber has a pH value of around 7. After mixing the glucose with the rest of the solution the mixture has a pH value of around 6.4, which offers an additional advantage in terms of tolerance by patients. 
     In WO 97/05852 a further development of this dialysis fluid is known in which the glucose is separated into two separate chambers, namely a second and third chamber, each with different concentrations. The concentrations are selected such that upon mixing the glucose from the second chamber with the rest of the solution in the first chamber, a dialysis fluid with a glucose concentration of 1.5% is obtained, upon mixing the clucose from the third chamber with the rest of the solution in the first chamber a glucose concentration of 2.5% is obtained, and upon mixing the glucose in the second and third chambers with the rest of the solution in the first chamber a glucose concentration of 4% is obtained. In this way, the three most useful glucose concentrations can be made available with one dialysis fluid recipient, which offers a great advantage in terms of logistics and storage. In addition, this dialysis fluid contains low amounts of degradation products as a result of the low pH values in the second and third chambers. 
     Although this already represents a clear reduction in the amount of degradation products in the dialysis fluid, there is still a significant amount of degradation products present owing to the high glucose concentration. As a result of the small quantities in the second and third chambers compared to that of the remaining solution in the first chamber, the glucose concentrations in these second and third chambers will be heated much faster during the heat sterilisation than the rest of the solution in the first chamber, which contains the remaining components. This leads to the glucose in the second and third chambers being held for an unnecessary long period at the sterilisation temperature, which results in the unnecessary increase in degradation products. Consequently, while a considerable reduction in degradation products is achieved compared to conventional dialysis fluids, the quantity of degradation products present is nevertheless still unnecessarily high. 
     Finally, it is also possible to reduce the formation of degradation products during heat sterilisation of multiple chamber recipients by means of a two step heating procedure. In this, the heating of the multiple chamber recipient in the autoclave is interrupted at a predetermined temperature, so that the temperatures in the first and second, and possibly the third, chamber can become essentially equal. Subsequently, the heating of the multiple chamber recipient proceeds to the predetermined sterilisation temperature. However, it is difficult with this procedure to find the exact intermediate temperature at which no, or only few, degradation products will be formed during the hold period. 
     DESCRIPTION OF THE INVENTION 
     In view of this background it is thus an object of the present invention to provide a method, whereby the degradation of heat sensitive components in medical substances during heat sterilisation is reduced, wherein the medical substances are contained in a multiple chamber recipient having a first chamber with a first medical substance and at least a second chamber with an amount of a second medical substance that is smaller relative to the first medical substance, and the multiple chamber recipient is heated to a predetermined temperature to sterilise the medical substances, is held at this temperature for a predetermined time and is subsequently cooled. 
     This object is achieved in that the second chamber with the second medical substance is thermally insulated during the heating of the multiple chamber recipient. 
     In this way, a method is provided that reduces the degradation of heat sensitive components in the second chamber during the heat sterilisation of multiple chamber recipients with different substances. The end product after mixing the contents of the chamber thus likewise contains substantially lower amounts of degradation products. 
     The second chamber can contain a quantity of a medical substance that is low relative to that in the first chamber. If this substance contains components that form degradation products when held for a long period at the sterilisation temperature, it will be prevented that they are heated faster and consequently remain at the sterilisation temperature longer than the substance in the first chamber. However, it is also possible that the second chamber contains the same amount of a medical substance as the first chamber, but with some of the components of this substance being very heat sensitive, so that they may be subjected to the sterilisation temperature only for a shorter period of time relative to the substance in the first chamber. By means of the thermal insulation of the second chamber, the heating of the second chamber can also be deliberately delayed, as a result of which the desired hold time at the sterilisation temperature can be set. 
     The hold time of the second chamber at the sterilisation temperature can advantageously be more precisely adjusted, in accordance with a preferred embodiment, when the thermal insulation is removed at a predetermined time after commencing the heating of the multiple chamber recipient. In this way the point in time at which the second chamber of the multiple chamber recipient is also exposed to the heating environment can be accurately set. Furthermore, since the point in time of the cooling of the multiple chamber recipient is also predetermined, a precisely controlled heat sterilisation with a defined hold time at the sterilisation temperature is also separately possible for the second chamber. 
     In accordance with a further preferred embodiment, the time for removing the thermal insulation is advantageously determined such that the first and second medical substances in the first and second chambers have essentially the same F value at the end of the hold time. F is utilised here as a gauge of the capacity of a sterilisation process to kill microbes, or the sterilisation capacity of a sterilisation process, and is predominantly utilised in the food industry and in medicine. It is a reference gauge and signifies a specific rate of microbes killed during a sterilisation process, F representing the time required to achieve this specific death rate at 121° C. 
     If the first and second medical substances have essentially the same F value, then this indicates that both substances have undergone essentially the same degree of sterilisation and, in particular, that the second chamber or the second substance has not been subjected to an unnecessary over-sterilisation as a result of overheating. Overheating the second chamber would lead to a substantial increase in the degradation products. It is to be noted at this point that a correlation exists between the F value and the degradation in the sense that with an increasing F value, the degradation products also increase, and vice versa. 
     In order to achieve an adequate sterilisation of the multiple chamber recipient, the latter is advantageously heated to a temperature of between 100° C. and 135° C., preferably to a temperature of 121° C. The sterilisation process is advantageously controlled such that the multiple chamber recipient is held for between 1 minute to several hours at this predetermined temperature, and preferably 15 minutes. 
     The method for reducing the degradation of heat sensitive components in medical substances described here is not limited only to multiple chamber recipients with two chambers, but may also be applied to multiple chamber recipients with more than two chambers. Therefore, according to another preferred embodiment, the method is utilised for a multiple chamber recipient that additionally includes a third chamber with an amount of a third medical substance that is smaller relative to that of the first medical substance, the third chamber being thermally insulated together with the second chamber during heating of the multiple chamber recipient. Here also the second chamber with the second medical substance and the third chamber with the third medical substance are advantageously arranged in a thermally insulating jacket, that is opened a predetermined time after commencing heating of the multiple chamber recipient. The second chamber and the third chamber can contain different amounts of the same substance or also the same amount of different substances. 
     The time at which the thermal insulation is removed is likewise advantageously defmed such that the first and second and third medical substances in the first and second and third chambers have essentially the same F value at the end of the hold time. If the second and third chambers contain different amounts of a medical substance, the F value of the largest amount is determinate for the removal of the thermal insulation. This should be essentially the same as the F value in the first chamber. The F value of the smaller amount in the other chamber will then be somewhat higher; this deviation from the desired F value has to be accepted in view of the required sterilisation of the larger amount. However, in order to achieve a nearly equivalent F value in this case also, the insulation can be formed differently in areas. For example, it could be formed thinner in the area of the second or third chamber, when these contain a larger amount, so that the sterilising heat reaches the large amount before the removal of the insulation and is able to heat this a little. Or, the second and third chambers will be respectively insulated such that the insulation of each can be successively removed independently of one another. 
     The thermally insulating jacket may take any desired form. For example, it can consist of an insulating material which, upon reaching a predetermined temperature will collapse or shrink, thus allowing the elevated surrounding temperature to reach the multiple chamber recipient. In this way the heating of the second and possibly also the third chamber will be delayed, and as a result, the time during which the second and possibly the third chamber are held at the sterilisation temperature can be controlled. 
     Another possibility for a thermally insulating jacket is a container with thermally insulating walls. The second and possibly the third chamber would be laid in this container with the first chamber remaining outside, and the container would be closed. In this manner, the second and possibly the third chamber will be thermally insulated, so that initially only the first chamber is heated. When the predetermined point in time is reached, the container is opened and the second chamber and possibly third chamber will be exposed to the sterilising heat and heated to the same temperature as the first chamber. In this way, the hold time of the second and possibly third chambers can be precisely determined independently of that of the first chamber. When the predetermined hold time of the first chamber is terminated, the multiple chamber recipient is cooled down. During this, care should be taken that the cooling occurs rapidly, so that degradation products are not formed unnecessarily as a result of slow cooling. 
     The method can be applied to multiple chamber recipients of any desired form, however it is advantageously utilised with a multiple chamber recipient formed as a flexible bag. The method can likewise be applied to multiple chamber recipients that hold any desired medical substance. For example, the multiple chamber recipient may hold substances for parenteral feeding. Also, the substances can take any desired form. For example, the medical substances can be solutions in liquid form, they can also be concentrates in powder form. However, the method is preferably applied to multiple chamber bags containing medical substances for the production of a dialysis fluid for peritoneal dialysis. According to a preferred embodiment, the second medical substance and third medical substance in the second and third chambers, respectively, comprise different concentrations of glucose, that is required for the dialysis fluid, or, according to another preferred embodiment, the same concentration of glucose in different quantities. 
    
    
     DESCRIPTION OF THE DRAWINGS 
     Examples for the method according to the invention are given by way of illustration in the accompanying drawings. The figures contained therein show the temperature curve and the F curve and thus the degradation, on the one hand, for the sterilisation of a double chamber bag according to conventional heat sterilisation in an autoclave, and on the other hand, for the heat sterilisation of a double chamber bag in an autoclave with the method according to the invention. Therein, the F value “F o ” is the F value corresponding to a sterilisation temperature of 121° C. There is shown in 
     FIG. 1 the temperature curve in °C. over time in minutes during the conventional heat sterilisation of a double chamber bag; 
     FIG. 2 the F o  value over time in minutes during the heat sterilisation according to FIG. 1; 
     FIG. 3 the temperature curve in ° C. over time in minutes during the heat sterilisation of a double chamber bag according to the method of the invention; 
     FIG. 4 the F o  value over the time in minutes during the heat sterilisation of FIG. 3; 
     FIG. 5 a double chamber bag; 
     FIG. 6 a triple chamber bag; 
     FIG. 7 an apparatus for carrying out the method according to the invention; and 
     FIG. 8 the apparatus of FIG. 7 in a closed state. 
    
    
     DESCRIPTION OF PREFERRED EMBODIMENTS 
     In FIG. 1 there is shown the temperature curve of a double chamber bag during a conventional heat sterilisation in an autoclave, wherein the dashed line  1  shows the temperature curve in the second chamber, and the continuous line  3  shows the temperature curve in the first chamber. The second chamber contains a smaller quantity of medical substance compared to the first chamber. Therefore, the contents of the second chamber will be heated faster during heating of the multiple chamber bag, as can be clearly seen from the temperature curve (line  1 ) in the second chamber during the first ten minutes. The second chamber reaches the sterilisation temperature, which here is about 121° C., much faster, and is also held there substantially longer than the first chamber. The first chamber needs a longer period for heating owing to the larger quantity of medical substance, as is evident from the temperature curve (line  3 ) during the first ten minutes. The first chamber reaches the sterilisation temperature much later and is also held at this sterilisation temperature for a shorter period (line  3 ). After reaching the end of the predetermined hold time at the sterilisation temperature for the multiple chamber recipient or for the first chamber, the multiple chamber recipient is cooled down. During this, the second chamber, or the contents of the second chamber, cools faster (line  1 ) owing to the smaller quantity of medical substance relative to that of the first chamber (line  3 ). The longer hold time of the second chamber at the sterilisation temperature causes a higher formation of degradation products and also leads to an elevated F value in the second chamber, which is superfluous in terms of sterilisation. 
     This is shown in FIG.  2 . FIG. 2 shows the F o  curve during the heat sterilisation according to FIG.  1 . As can be clearly seen here, in the second chamber (line  1 ) an F 0  value is obtained that is almost double that in chamber  1  (line  3 ). The F o  value of about ten obtained in chamber  1  is a normally sought and sufficient F o  value for sterilisation, while the F o  value obtained in the second chamber of around twenty is unnecessarily high. 
     To avoid this over-sterilisation and the accompanying increased degradation of, for example, glucose contained in the second chamber, the second chamber is provided with a thermally insulating jacket, that is removed a predetermined time after the beginning of the heating process. The resulting temperature curve during heat sterilisation is shown in FIG.  3 . Here it can be seen clearly that the beginning of the heating of the second chamber (line  2 ) is markedly delayed compared to the beginning of the heating of the first chamber (line  3 ). After about twenty minutes, the thermally insulating jacket of the second chamber is removed, so that the second chamber is likewise heated rapidly to the sterilisation temperature, together with the first chamber. After a predetermined hold time of the multiple chamber recipient at the sterilisation temperature, the multiple chamber recipient is cooled, as is apparent from the continuing temperature curve of the first and second chambers (line  3 , line  1 ). 
     In contrast to the heat sterilisation of the multiple chamber recipient without the thermal insulation of the second chamber according to FIG. 1, the second chamber here remains held at the sterilisation temperature essentially as long as the first chamber. In this way, on the one hand, the excessive and unnecessary formation of degradation products is prevented and, on the other, an over-sterilisation of the medical substance contained in the second chamber is avoided. 
     This is shown in FIG.  4 . FIG. 4 shows the F o  curve during the heat sterilisation according to FIG.  3 . Because the first and second chambers, or their contents, are held for essentially the same time at the sterilisation temperature, the result is an almost identical F o  value. The F o  value of the medical substance in the second chamber (line  1 ) differs only slightly from the F o  value of the substance in the first chamber (line  3 ). Due to the later commencement of heating and the slightly higher temperature relative to that of the first chamber during the hold time, the F o  temperature curve of the second chamber (line  1 ) lies slightly below the F o  temperature curve of the first chamber (line  3 ) at the beginning, but then lies slightly above it at the end of the sterilisation. However an over-sterilisation of the second chamber has not occurred, nor were excessive degradation products formed in the second chamber during the sterilisation. 
     The method performed here by way of example on a two chamber bag can also be applied to three or multiple chamber bags, as described in detail above. In this case, the larger first chamber, or the first chamber filled with the larger amount of medical substance, determines the hold time of the multiple chamber bag in the autoclave, while the chamber of the second, and possibly third, fourth, etc. chambers provided with a thermally insulating jacket that includes the largest amount of medical substance, determines the time of removal of the thermally insulating jacket. The desired, lowest required F value, that corresponds to an adequate sterilisation, is always to be selected as a gauge for the hold time of the multiple chamber recipient in the autoclave or for the removal of the thermal insulation. 
     In FIG. 5 a double chamber bag  10  is shown, that is to be sterilised according to the method of the invention. The multiple chamber bag  10  includes a first larger chamber  12  and a second smaller chamber  14 . In the present case, the multiple chamber recipient  10  contains a dialysis solution for peritoneal dialysis and includes an electrolytic solution in the first chamber  12  and a glucose solution in the second chamber  14 . 
     The first chamber  12  is separated from the second chamber  14  by a welded seam  16 , in which there is arranged a connecting tube  26 . The connecting tube  26  is closed at one end by a break-off seal  28 . A fill tube  20 , through which the second chamber  14  is filled, is connected at the upper edge  18  of the multiple chamber recipient  10 . The outer end of the fill tube  20  is provided with a seal  22  which may be achieved simply by melting the end of the fill tube  20  for example. Moreover, at the upper edge  18  there is provided an opening  24 , by which the multiple recipient bag  10  can be suspended. At the lower edge  30  of the multiple chamber recipient  10 , there is arranged a connection tube  32 , by means of which the contents of the first chamber  12  can be supplied to a patient, who is not shown. Furthermore, there is also provided a fill tube  20  at the lower edge  30 , through which the first chamber  12  is filled. This fill tube  20  is also provided with a seal  22  at its outer end. Finally, a feed tube  34  is also arranged at the lower edge  30 , by means of which medication can be supplied to the contents of the first chamber  12 , for example. The feed tube  34  is closed at its outer end with a septum  36 , so that the injection of medication into the first chamber  12  is possible. Before the dialysis solution is administered to the patient, the contents of the first chamber  12  and second chamber  14  are mixed together. To this end, the break-off seal  28  is broken off so that the connecting tube  26  between the first chamber  12  and the second chamber  14  is opened. The contents of the second chamber  14  then run through the connecting tube  26  into the first chamber  12 , and mix with the solution located therein. Subsequently, the mixed solution can be supplied to the patient through the connecting tube  32 . 
     It is again to be noted at this point that the multiple chamber recipient  10  can also include a third, or even more chambers, the contents of which would also be mixed with the contents of the first chamber  12  to obtain the desired solution. As an example of this, a triple chamber bag  60  is shown in FIG.  6 . 
     This includes a third chamber  50  that is separated from the second chamber  14  by a welded seam  52 . By means of a fill tube  20 , that is likewise provided here, the third chamber  50  can be filled, and by means of a connecting tube  26 , its contents can be fed into the first chamber  12  for mixing with the contents of the first chamber. Otherwise, like parts are denoted by like reference numerals so that a further description can be dispensed with. 
     In FIG. 7 there is shown an apparatus  40  for insulating the second chamber of the multiple chamber recipient  10  during the heat sterilisation. The apparatus includes an upper portion  42  and a lower portion  44  that are connected together by a joint  46 . The upper portion  42  and the lower portion  44  are each box-shaped and comprise thermal insulation  48  on their inner sides. 
     The multiple chamber recipient  10 , that has already been described extensively with reference to FIG. 5, is laid with its first chamber  14  in the lower portion  44  of the apparatus  40 . Care should be taken when doing this that the multiple chamber recipient  10  lies with the welded seam  16  on the edge of the lower portion  44 . If the multiple chamber recipient  10  were to comprise several chambers requiring thermal insulation during the heat sterilisation of the multiple chamber recipient  10 , these would also be arranged in the lower portion  44  of the apparatus  40 . 
     When the apparatus  40  is closed by lowering the upper portion  42  down on the lower portion  44 , the second chamber  14  of the multiple chamber recipient  10  is thermally insulated. This is shown in FIG.  8 . 
     If the multiple chamber recipient  10  shown here is heat sterilised, for example in an autoclave, with its second chamber  14  thermally insulated by means of the apparatus  40 , initially only the first chamber  12  will be heated. After the elapse of a predetermined time, the apparatus  40  will be opened by raising the upper portion  42 , which can be achieved by appropriate means known to the person skilled in the art (this open condition corresponds approximately to that of the open apparatus  40  shown in FIG.  7 ). Hence the second chamber  14  of the multiple chamber recipient  10  will also be exposed to the sterilisation temperature and heated. In this way the hold time of the second chamber  14  at the sterilisation temperature can be intentionally controlled, as described in detail above. 
     List of Reference Numerals 
     
       
         
               
               
             
           
               
                   
               
             
             
               
                 10 
                 bag 
               
               
                 12 
                 first chamber 
               
               
                 14 
                 second chamber 
               
               
                 16 
                 welded seam 
               
               
                 18 
                 upper edge 
               
               
                 20 
                 fill tube 
               
               
                 22 
                 seal 
               
               
                 24 
                 opening 
               
               
                 26 
                 connecting tube 
               
               
                 28 
                 break-off seal 
               
               
                 30 
                 lower edge 
               
               
                 32 
                 connecting tube 
               
               
                 34 
                 feed tube 
               
               
                 36 
                 septum 
               
               
                 40 
                 apparatus 
               
               
                 42 
                 upper portion 
               
               
                 44 
                 lower portion 
               
               
                 46 
                 joint 
               
               
                 48 
                 thermal insulation 
               
               
                 50 
                 third chamber 
               
               
                 52 
                 welded seam 
               
               
                 60 
                 triple chamber bag